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14 pages, 4785 KiB

Open AccessArticle

Electrophysiological Effects of the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor Dapagliflozin on Human Cardiac Potassium Channels

by Mara Elena Müller, Finn Petersenn, Juline Hackbarth, Julia Pfeiffer, Heike Gampp, Norbert Frey, Patrick Lugenbiel, Dierk Thomas and Ann-Kathrin Rahm

Int. J. Mol. Sci. 2024, 25(11), 5701; https://doi.org/10.3390/ijms25115701 - 23 May 2024

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Abstract

The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be [...] Read more.

The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K⁺) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K_v11.1, K_v1.5, K_v4.3, K_ir2.1, K_2P2.1, K_2P3.1, and K_2P17.1, contributing to I_Kur, I_to, I_Kr, I_K1, and I_K2P K⁺ currents. Human channels coded by KCNH2, KCNA5, KCND3, KCNJ2, KCNK2, KCNK3, and KCNK17 were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K_v11.1 and K_v1.5 currents, whereas K_ir2.1, K_2P2.1, and K_2P17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K_v4.3 or K_2P3.1 K⁺ channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current–voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K⁺ channels underlying I_Kur, I_Kr, I_K1, and I_K2P currents. Substantial activation of K_2P2.1 and K_2P17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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18 pages, 3268 KiB

Open AccessArticle

PD-L1 and AKT Overexpressing Adipose-Derived Mesenchymal Stem Cells Enhance Myocardial Protection by Upregulating CD25⁺ T Cells in Acute Myocardial Infarction Rat Model

by Yu-Kai Lin, Lien-Cheng Hsiao, Mei-Yao Wu, Yun-Fang Chen, Yen-Nien Lin, Chia-Ming Chang, Wei-Hsin Chung, Ke-Wei Chen, Chiung-Ray Lu, Wei-Yu Chen, Shih-Sheng Chang, Woei-Cheang Shyu, An-Sheng Lee, Chu-Huang Chen, Long-Bin Jeng and Kuan-Cheng Chang

Int. J. Mol. Sci. 2024, 25(1), 134; https://doi.org/10.3390/ijms25010134 - 21 Dec 2023

Cited by 3 | Viewed by 1602

Abstract

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, [...] Read more.

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure–volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure–volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25⁺ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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16 pages, 3277 KiB

Open AccessArticle

Integrated Bioinformatics Analysis Confirms the Diagnostic Value of Nourin-Dependent miR-137 and miR-106b in Unstable Angina Patients

by Salwa A. Elgebaly, W. Frank Peacock, Robert H. Christenson, Donald L. Kreutzer, Ahmed Hassan Ibrahim Faraag, Amir Mahfouz Mokhtar Sarguos and Nashwa El-Khazragy

Int. J. Mol. Sci. 2023, 24(19), 14783; https://doi.org/10.3390/ijms241914783 - 30 Sep 2023

Cited by 1 | Viewed by 2031

Abstract

The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. [...] Read more.

The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. The Nourin protein is rapidly expressed in patients with acute coronary syndrome (ACS) (UA and acute myocardial infarction (AMI)). MicroRNAs regulate gene expression through mRNA binding and, thus, may represent potential biomarkers. We initially identified miR-137 and miR-106b and conducted a clinical validation, which demonstrated that they were highly upregulated in ACS patients, but not in healthy subjects and non-ACS controls. Using integrated comprehensive bioinformatics analysis, the present study confirms that the Nourin protein targets miR-137 and miR-106b, which are linked to myocardial ischemia and inflammation associated with ACS. Molecular docking demonstrated robust interactions between the Nourin protein and miR137/hsa-miR-106b, involving hydrogen bonds and hydrophobic interactions, with −10 kcal/mol binding energy. I-TASSER generated Nourin analogs, with the top 10 chosen for structural insights. Antigenic regions and MHCII epitopes within the Nourin SPGADGNGGEAMPGG sequence showed strong binding to HLA-DR/DQ alleles. The Cytoscape network revealed interactions of -miR137/hsa-miR--106b and Phosphatase and tensin homolog (PTEN) in myocardial ischemia. RNA Composer predicted the secondary structure of miR-106b. Schrödinger software identified key Nourin-RNA interactions critical for complex stability. The study identifies miR-137 and miR-106b as potential ACS diagnostic and therapeutic targets. This research underscores the potential of miRNAs targeting Nourin for precision ACS intervention. The analysis leverages RNA Composer, Schrödinger, and I-TASSER tools to explore interactions and structural insights. Robust Nourin-miRNA interactions are established, bolstering the case for miRNA-based interventions in ischemic injury. In conclusion, the study contributes to UA and AMI diagnosis strategies through bioinformatics-guided exploration of Nourin-targeting miRNAs. Supported by comprehensive molecular analysis, the hypoxia-induced miR-137 for cell apoptosis (a marker of cell damage) and the inflammation-induced miR-106b (a marker of inflammation) confirmed their potential clinical use as diagnostic biomarkers. This research reinforces the growing role of miR-137/hsa-miR-106b in the early diagnosis of myocardial ischemia in unstable angina patients. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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16 pages, 2975 KiB

Open AccessArticle

Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac K_v4.3 (I_to) Channel Isoforms

by Ann-Kathrin Rahm, Juline Hackbarth, Mara E. Müller, Julia Pfeiffer, Heike Gampp, Finn Petersenn, Rasmus Rivinius, Norbert Frey, Patrick Lugenbiel and Dierk Thomas

Int. J. Mol. Sci. 2023, 24(18), 13842; https://doi.org/10.3390/ijms241813842 - 8 Sep 2023

Viewed by 1874

Abstract

Cardiac K_v4.3 channels contribute to the transient outward K⁺ current, I_to, during early repolarization of the cardiac action potential. Two different isoforms of K_v4.3 are present in the human ventricle and exhibit differential remodeling in heart [...] Read more.

Cardiac K_v4.3 channels contribute to the transient outward K⁺ current, I_to, during early repolarization of the cardiac action potential. Two different isoforms of K_v4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K_v4.3 isoforms to explore their potential for isoform-specific therapy. K_v4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K_v4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K_v4.3 L by 77 ± 2% and K_v4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K_v4.3 L) and 35 ± 4% (K_v4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K_v4.3 protein expression. Carvedilol inhibited K_v4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K_v4.3. Blockade of repolarizing K_v4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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17 pages, 6691 KiB

Open AccessArticle

Knockout of the Cardiac Transcription Factor NKX2-5 Results in Stem Cell-Derived Cardiac Cells with Typical Purkinje Cell-like Signal Transduction and Extracellular Matrix Formation

by Paul Disse, Isabel Aymanns, Lena Mücher, Sarah Sandmann, Julian Varghese, Nadine Ritter, Nathalie Strutz-Seebohm, Guiscard Seebohm and Stefan Peischard

Int. J. Mol. Sci. 2023, 24(17), 13366; https://doi.org/10.3390/ijms241713366 - 29 Aug 2023

Cited by 2 | Viewed by 1703

Abstract

The human heart controls blood flow, and therewith enables the adequate supply of oxygen and nutrients to the body. The correct function of the heart is coordinated by the interplay of different cardiac cell types. Thereby, one can distinguish between cells of the [...] Read more.

The human heart controls blood flow, and therewith enables the adequate supply of oxygen and nutrients to the body. The correct function of the heart is coordinated by the interplay of different cardiac cell types. Thereby, one can distinguish between cells of the working myocardium, the pace-making cells in the sinoatrial node (SAN) and the conduction system cells in the AV-node, the His-bundle or the Purkinje fibres. Tissue-engineering approaches aim to generate hiPSC-derived cardiac tissues for disease modelling and therapeutic usage with a significant improvement in the differentiation quality of myocardium and pace-making cells. The differentiation of cells with cardiac conduction system properties is still challenging, and the produced cell mass and quality is poor. Here, we describe the generation of cardiac cells with properties of the cardiac conduction system, called conduction system-like cells (CSLC). As a primary approach, we introduced a CrispR-Cas9-directed knockout of the NKX2-5 gene in hiPSC. NKX2-5-deficient hiPSC showed altered connexin expression patterns characteristic for the cardiac conduction system with strong connexin 40 and connexin 43 expression and suppressed connexin 45 expression. Application of differentiation protocols for ventricular- or SAN-like cells could not reverse this connexin expression pattern, indicating a stable regulation by NKX2-5 on connexin expression. The contraction behaviour of the hiPSC-derived CSLCs was compared to hiPSC-derived ventricular- and SAN-like cells. We found that the contraction speed of CSLCs resembled the expected contraction rate of human conduction system cells. Overall contraction was reduced in differentiated cells derived from NKX2-5 knockout hiPSC. Comparative transcriptomic data suggest a specification of the cardiac subtype of CSLC that is distinctly different from ventricular or pacemaker-like cells with reduced myocardial gene expression and enhanced extracellular matrix formation for improved electrical insulation. In summary, knockout of NKX2-5 in hiPSC leads to enhanced differentiation of cells with cardiac conduction system features, including connexin expression and contraction behaviour. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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24 pages, 11403 KiB

Open AccessArticle

Deletion of Smooth Muscle O-GlcNAc Transferase Prevents Development of Atherosclerosis in Western Diet-Fed Hyperglycemic ApoE^-/- Mice In Vivo

by Saugat Khanal, Neha Bhavnani, Amy Mathias, Jason Lallo, Shreya Gupta, Vahagn Ohanyan, Jessica M. Ferrell and Priya Raman

Int. J. Mol. Sci. 2023, 24(9), 7899; https://doi.org/10.3390/ijms24097899 - 26 Apr 2023

Cited by 3 | Viewed by 2251

Abstract

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of [...] Read more.

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of O-GlcNAc signaling, in the evolution of diabetic atherosclerosis remains elusive. The goal of this study was to determine whether smooth muscle OGT (smOGT) plays a direct role in hyperglycemia-induced atherosclerotic lesion formation and SMC de-differentiation. Using tamoxifen-inducible Myh11-CreER^T2 and Ogt^fl/fl mice, we generated smOGT^WT and smOGT^KO mice, with and without ApoE-null backgrounds. Following STZ-induced hyperglycemia, smOGT^WT and smOGT^KO mice were kept on a standard laboratory diet for the study duration. In a parallel study, smOGT^WTApoE^-/- and smOGT^KOApoE^-/- were initiated on Western diet at 8-wks-age. Animals harvested at 14–16-wks-age were used for plasma and tissue collection. Loss of smOGT augmented SM contractile marker expression in aortic vessels of STZ-induced hyperglycemic smOGT^KO mice. Consistently, smOGT deletion attenuated atherosclerotic lesion lipid burden (Oil red O), plaque area (H&E), leukocyte (CD45) and smooth muscle cell (ACTA2) abundance in Western diet-fed hyperglycemic smOGT^KOApoE^-/- mice. This was accompanied by increased SM contractile markers and reduced inflammatory and proliferative marker expression. Further, smOGT deletion attenuated YY1 and SRF expression (transcriptional regulators of SM contractile genes) in hyperglycemic smOGT^KOApoE^-/- and smOGT^KO mice. These data uncover an athero-protective outcome of smOGT loss-of-function and suggest a direct regulatory role of OGT-mediated O-GlcNAcylation in VSMC de-differentiation in hyperglycemia. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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24 pages, 2715 KiB

Open AccessArticle

Lifetime Evaluation of Left Ventricular Structure and Function in Male C57BL/6J Mice after Gamma and Space-Type Radiation Exposure

by Agnieszka Brojakowska, Cedric J. Jackson, Malik Bisserier, Mary K. Khlgatian, Cynthia Grano, Steve R. Blattnig, Shihong Zhang, Kenneth M. Fish, Vadim Chepurko, Elena Chepurko, Virginia Gillespie, Ying Dai, Brooke Lee, Venkata Naga Srikanth Garikipati, Lahouaria Hadri, Raj Kishore and David A. Goukassian

Int. J. Mol. Sci. 2023, 24(6), 5451; https://doi.org/10.3390/ijms24065451 - 13 Mar 2023

Cited by 3 | Viewed by 26434

Abstract

The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically 5-ion simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. Three-month-old, age-matched, male C57BL/6J mice were irradiated with ¹³⁷ [...] Read more.

The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically 5-ion simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. Three-month-old, age-matched, male C57BL/6J mice were irradiated with ¹³⁷Cs gamma (γ; 100, 200 cGy) and simGCRsim (50 and 100 cGy). LV function was assessed via transthoracic echocardiography at 14 and 28 days (early), and at 365, 440, and 660 (late) days post IR. We measured the endothelial function marker brain natriuretic peptide in plasma at three late timepoints. We assessed the mRNA expression of the genes involved in cardiac remodeling, fibrosis, inflammation, and calcium handling in LVs harvested at 660 days post IR. All IR groups had impaired global LV systolic function at 14, 28, and 365 days. At 660 days, 50 cGy simGCRsim-IR mice exhibited preserved LV systolic function with altered LV size and mass. At this timepoint, the simGCRsim-IR mice had elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers Tgfβ1, Mcp1, Mmp9, and βmhc, suggesting that space-type IR may induce the cardiac remodeling processes that are commonly associated with diastolic dysfunction. IR groups showing statistical significance were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). The observed dose-response shape did not indicate a lower threshold at these IR doses. A single full-body IR at doses of 100–200 cGy for γ-IR, and 50–100 cGy for simGCRsim-IR decreases the global LV systolic function in WT mice as early as 14 and 28 days after exposure, and at 660 days post IR. Interestingly, there is an intermediate time point (365 days) where the impairment in LV function is observed. These findings do not exclude the possibility of increased acute or degenerative cardiovascular disease risks at lower doses of space-type IR, and/or when combined with other space travel-associated stressors such as microgravity. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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13 pages, 3301 KiB

Open AccessArticle

BGP-15 Protects against Doxorubicin-Induced Cell Toxicity via Enhanced Mitochondrial Function

by Alexandra Gyongyosi, Nikolett Csaki, Agota Peto, Kitti Szoke, Ferenc Fenyvesi, Ildiko Bacskay and Istvan Lekli

Int. J. Mol. Sci. 2023, 24(6), 5269; https://doi.org/10.3390/ijms24065269 - 9 Mar 2023

Cited by 3 | Viewed by 1861

Abstract

Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, [...] Read more.

Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, and autophagy dysregulation. BGP-15 has a wide range of cytoprotective effects, including mitochondrial protection, but up to now, there is no information about any of its beneficial effects on DOX-induced cardiotoxicity. In this study, we investigated whether the protective effects of BGP-15 pretreatment are predominantly via preserving mitochondrial function, reducing mitochondrial ROS production, and if it has an influence on autophagy processes. H9c2 cardiomyocytes were pretreated with 50 μM of BGP-15 prior to different concentrations (0.1; 1; 3 μM) of DOX exposure. We found that BGP-15 pretreatment significantly improved the cell viability after 12 and 24 h DOX exposure. BGP-15 ameliorated lactate dehydrogenase (LDH) release and cell apoptosis induced by DOX. Additionally, BGP-15 pretreatment attenuated the level of mitochondrial oxidative stress and the loss of mitochondrial membrane potential. Moreover, BGP-15 further slightly modulated the autophagic flux, which was measurably decreased by DOX treatment. Hence, our findings clearly revealed that BGP-15 might be a promising agent for alleviating the cardiotoxicity of DOX. This critical mechanism appears to be given by the protective effect of BGP-15 on mitochondria. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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16 pages, 2532 KiB

Open AccessArticle

Effect of SARS-CoV-2 mRNA-Vaccine on the Induction of Myocarditis in Different Murine Animal Models

by Vanessa A. Zirkenbach, Rebecca M. Ignatz, Renate Öttl, Zeynep Cehreli, Vera Stroikova, Mansur Kaya, Lorenz H. Lehmann, Michael R. Preusch, Norbert Frey and Ziya Kaya

Int. J. Mol. Sci. 2023, 24(5), 5011; https://doi.org/10.3390/ijms24055011 - 6 Mar 2023

Cited by 5 | Viewed by 3032

Abstract

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the [...] Read more.

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the risk and safety of vaccination, especially in patients who are already diagnosed with acute/chronic (autoimmune) myocarditis from other causes, such as viral infections, or as a side effect of medication and treatment. Thus, the risk and safety of these vaccines, in combination with other therapies that could induce myocarditis (e.g., immune checkpoint inhibitor (ICI) therapy), are still poorly assessable. Therefore, vaccine safety, with respect to worsening myocardial inflammation and myocardial function, was studied in an animal model of experimentally induced autoimmune myocarditis. Furthermore, it is known that ICI treatment (e.g., antibodies (abs) against PD-1, PD-L1, and CTLA-4, or a combination of those) plays an important role in the treatment of oncological patients. However, it is also known that treatment with ICIs can induce severe, life-threatening myocarditis in some patients. Genetically different A/J (most susceptible strain) and C57BL/6 (resistant strain) mice, with diverse susceptibilities for induction of experimental autoimmune myocarditis (EAM) at various age and gender, were vaccinated twice with SARS-CoV-2 mRNA-vaccine. In an additional A/J group, an autoimmune myocarditis was induced. In regard to ICIs, we tested the safety of SARS-CoV-2 vaccination in PD-1^−/− mice alone, and in combination with CTLA-4 abs. Our results showed no adverse effects related to inflammation and heart function after mRNA-vaccination, independent of age, gender, and in different mouse strains susceptible for induction of experimental myocarditis. Moreover, there was no worsening effect on inflammation and cardiac function when EAM in susceptible mice was induced. However, in the experiments with vaccination and ICI treatment, we observed, in some mice, low elevation of cardiac troponins in sera, and low scores of myocardial inflammation. In sum, mRNA-vaccines are safe in a model of experimentally induced autoimmune myocarditis, but patients undergoing ICI therapy should be closely monitored when vaccinated. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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18 pages, 20119 KiB

Open AccessArticle

Effects of Cardiac Stem Cell on Postinfarction Arrhythmogenic Substrate

by Ángel Arenal, Gonzalo R. Ríos-Muñoz, Alejandro Carta-Bergaz, Pablo M. Ruiz-Hernández, Esther Pérez-David, Verónica Crisóstomo, Gerard Loughlin, Ricardo Sanz-Ruiz, Javier Fernández-Portales, Alejandra Acosta, Claudia Báez-Díaz, Virginia Blanco-Blázquez, María J. Ledesma-Carbayo, Miriam Pareja, María E. Fernández-Santos, Francisco M. Sánchez-Margallo, Javier G. Casado and Francisco Fernández-Avilés

Int. J. Mol. Sci. 2022, 23(24), 16211; https://doi.org/10.3390/ijms232416211 - 19 Dec 2022

Cited by 1 | Viewed by 2402

Abstract

Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the [...] Read more.

Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n: 10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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16 pages, 1847 KiB

Open AccessArticle

Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial

by Felicitas Stoll, Andrea Seidel-Glätzer, Ina Burghaus, Oliver Göring, Max Sauter, Peter Rose, Volker Daniel, Mathias Haag, Matthias Schwab, Johannes Riffel, Florian André, Lenka Taylor, Johanna Weiss, Jürgen Burhenne, Volker Cleeves, Walter E. Haefeli and Antje Blank

Int. J. Mol. Sci. 2022, 23(24), 15924; https://doi.org/10.3390/ijms232415924 - 14 Dec 2022

Cited by 6 | Viewed by 2019

Abstract

Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma [...] Read more.

Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges–Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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11 pages, 2703 KiB

Open AccessArticle

Effects of Adrenomedullin on Atrial Electrophysiology and Pulmonary Vein Arrhythmogenesis

by Chye-Gen Chin, Ahmed Moustafa Elimam, Fong-Jhih Lin, Yao-Chang Chen, Yung-Kuo Lin, Yen-Yu Lu, Satoshi Higa, Shih-Ann Chen, Ming-Hsiung Hsieh and Yi-Jen Chen

Int. J. Mol. Sci. 2022, 23(22), 14064; https://doi.org/10.3390/ijms232214064 - 15 Nov 2022

Viewed by 1565

Abstract

Adrenomedullin, a peptide with vasodilatory, natriuretic, and diuretic effects, may be a novel agent for treating heart failure. Heart failure is associated with an increased risk of atrial fibrillation (AF), but the effects of adrenomedullin on atrial arrhythmogenesis remain unclear. This study investigated [...] Read more.

Adrenomedullin, a peptide with vasodilatory, natriuretic, and diuretic effects, may be a novel agent for treating heart failure. Heart failure is associated with an increased risk of atrial fibrillation (AF), but the effects of adrenomedullin on atrial arrhythmogenesis remain unclear. This study investigated whether adrenomedullin modulates the electrophysiology of the atria (AF substrate) or pulmonary vein (PV; AF trigger) arrhythmogenesis. Conventional microelectrode or whole-cell patch clamps were used to study the effects of adrenomedullin (10, 30, and 100 pg/mL) on the electrical activity, mechanical response, and ionic currents of isolated rabbit PV and sinoatrial node tissue preparations and single PV cardiomyocytes. At 30 and 100 pg/mL, adrenomedullin significantly reduced the spontaneous beating rate of the PVs from 2.0 ± 0.4 to 1.3 ± 0.5 and 1.1 ± 0.5 Hz (reductions of 32.9% ± 7.1% and 44.9 ± 8.4%), respectively, and reduced PV diastolic tension by 12.8% ± 4.1% and 14.5% ± 4.1%, respectively. By contrast, adrenomedullin did not affect sinoatrial node beating. In the presence of L-NAME (a nitric oxide synthesis inhibitor, 100 μM), adrenomedullin (30 pg/mL) did not affect the spontaneous beating rate or diastolic tension of the PVs. In the single-cell experiments, adrenomedullin (30 pg/mL) significantly reduced the L-type calcium current (I_Ca-L) and reverse-mode current of the sodium–calcium exchanger (NCX). Adrenomedullin reduces spontaneous PV activity and PV diastolic tension by reducing I_Ca-L and NCX current and thus may be useful for treating atrial tachyarrhythmia. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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16 pages, 2242 KiB

Open AccessArticle

Alterations of the Sialylation Machinery in Brugada Syndrome

by Andrea Ghiroldi, Giuseppe Ciconte, Pasquale Creo, Adriana Tarantino, Dario Melgari, Sara D’Imperio, Marco Piccoli, Federica Cirillo, Emanuele Micaglio, Michelle M. Monasky, Anthony Frosio, Emanuela T. Locati, Gabriele Vicedomini, Ilaria Rivolta, Carlo Pappone and Luigi Anastasia

Int. J. Mol. Sci. 2022, 23(21), 13154; https://doi.org/10.3390/ijms232113154 - 29 Oct 2022

Cited by 2 | Viewed by 1847

Abstract

Brugada Syndrome (BrS) is an inherited arrhythmogenic disorder with an increased risk of sudden cardiac death. Recent evidence suggests that BrS should be considered as an oligogenic or polygenic condition. Mutations in genes associated with BrS are found in about one-third of patients [...] Read more.

Brugada Syndrome (BrS) is an inherited arrhythmogenic disorder with an increased risk of sudden cardiac death. Recent evidence suggests that BrS should be considered as an oligogenic or polygenic condition. Mutations in genes associated with BrS are found in about one-third of patients and they mainly disrupt the cardiac sodium channel NaV1.5, which is considered the main cause of the disease. However, voltage-gated channel’s activity could be impacted by post-translational modifications such as sialylation, but their role in BrS remains unknown. Thus, we analyzed high risk BrS patients (n = 42) and healthy controls (n = 42) to assess an involvement of sialylation in BrS. Significant alterations in gene expression and protein sialylation were detected in Peripheral Blood Mononuclear Cells (PBMCs) from BrS patients. These changes were significantly associated with the phenotypic expression of the disease, as the size of the arrhythmogenic substrate and the duration of epicardial electrical abnormalities. Moreover, protein desialylation caused a reduction in the sodium current in an in vitro NaV1.5-overexpressing model. Dysregulation of the sialylation machinery provides definitive evidence that BrS affects extracardiac tissues, suggesting an underlying cause of the disease. Moreover, detection of these changes at the systemic level and their correlation with the clinical phenotype hint at the existence of a biomarker signature for BrS. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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14 pages, 2566 KiB

Open AccessArticle

Blockade of Wnt Secretion Attenuates Myocardial Ischemia–Reperfusion Injury by Modulating the Inflammatory Response

by Ingmar Sören Meyer, Xue Li, Carina Meyer, Oksana Voloshanenko, Susann Pohl, Michael Boutros, Hugo Albert Katus, Norbert Frey and Florian Leuschner

Int. J. Mol. Sci. 2022, 23(20), 12252; https://doi.org/10.3390/ijms232012252 - 14 Oct 2022

Cited by 7 | Viewed by 2626

Abstract

Wnt (a portmanteau of Wingless and Int-1) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion [...] Read more.

Wnt (a portmanteau of Wingless and Int-1) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion inhibitor LGK-974 on MI healing. Ischemia/reperfusion (I/R) injury was induced in mice and Wnt signaling was inhibited by oral administration of the porcupine inhibitor LGK-974. The transcriptome was analyzed from infarcted tissue by using RNA sequencing analysis. The inflammatory response after I/R was evaluated by flow cytometry. Heart function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Transcriptome and gene set enrichment analysis revealed a modulation of the inflammatory response upon administration of the Wnt secretion inhibitor LGK-974 following I/R. In addition, LGK-974-treated animals showed an attenuated inflammatory response and improved heart function. In an in vitro model of hypoxic cardiomyocyte and monocyte/macrophage interaction, LGK974 inhibited the activation of Wnt signaling in monocytes/macrophages and reduced their pro-inflammatory phenotype. We here show that Wnt signaling affects inflammatory processes after MI. The Wnt secretion inhibitor LGK-974 appears to be a promising compound for future immunomodulatory approaches to improve cardiac remodeling after MI. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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11 pages, 1025 KiB

Open AccessArticle

Genotype Complements the Phenotype: Identification of the Pathogenicity of an LMNA Splice Variant by Nanopore Long-Read Sequencing in a Large DCM Family

by Farbod Sedaghat-Hamedani, Sabine Rebs, Elham Kayvanpour, Chenchen Zhu, Ali Amr, Marion Müller, Jan Haas, Jingyan Wu, Lars M. Steinmetz, Philipp Ehlermann, Katrin Streckfuss-Bömeke, Norbert Frey and Benjamin Meder

Int. J. Mol. Sci. 2022, 23(20), 12230; https://doi.org/10.3390/ijms232012230 - 13 Oct 2022

Cited by 4 | Viewed by 2244

Abstract

Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20–40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used [...] Read more.

Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20–40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used a combination of NGS, human-induced pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and nanopore long-read sequencing to identify the causal variant in a multi-generational pedigree of DCM. A four-generation family with familial DCM was investigated. Next-generation sequencing (NGS) was performed on 22 family members. Skin biopsies from two affected family members were used to generate iPSCs, which were then differentiated into iPSC-CMs. Short-read RNA sequencing was used for the evaluation of the target gene expression, and long-read RNA nanopore sequencing was used to evaluate the relevance of the splice variants. The pedigree suggested a highly penetrant, autosomal dominant mode of inheritance. The phenotype of the family was suggestive of laminopathy, but previous genetic testing using both Sanger and panel sequencing only yielded conflicting evidence for LMNA p.R644C (rs142000963), which was not fully segregated. By re-sequencing four additional affected family members, further non-coding LMNA variants could be detected: rs149339264, rs199686967, rs201379016, and rs794728589. To explore the roles of these variants, iPSC-CMs were generated. RNA sequencing showed the LMNA expression levels to be significantly lower in the iPSC-CMs of the LMNA variant carriers. We demonstrated a dysregulated sarcomeric structure and altered calcium homeostasis in the iPSC-CMs of the LMNA variant carriers. Using targeted nanopore long-read sequencing, we revealed the biological significance of the variant c.356+1G>A, which generates a novel 5′ splice site in exon 1 of the cardiac isomer of LMNA, causing a nonsense mRNA product with almost complete RNA decay and haploinsufficiency. Using novel molecular analysis and nanopore technology, we demonstrated the pathogenesis of the rs794728589 (c.356+1G>A) splice variant in LMNA. This study highlights the importance of precise diagnostics in the clinical management and workup of cardiomyopathies. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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18 pages, 8103 KiB

Open AccessArticle

PINK1 Phosphorylates Drp1^S616 to Improve Mitochondrial Fission and Inhibit the Progression of Hypertension-Induced HFpEF

by Jian Shou and Yunlong Huo

Int. J. Mol. Sci. 2022, 23(19), 11934; https://doi.org/10.3390/ijms231911934 - 8 Oct 2022

Cited by 10 | Viewed by 2890

Abstract

(1) Background: Heart failure with preserved ejection fraction (HFpEF) is a major subtype of HF with no effective treatments. Mitochondrial dysfunctions relevant to the imbalance of fusion and fission occur in HFpEF. Drp1 is a key protein regulating mitochondrial fission, and PINK1 is [...] Read more.

(1) Background: Heart failure with preserved ejection fraction (HFpEF) is a major subtype of HF with no effective treatments. Mitochondrial dysfunctions relevant to the imbalance of fusion and fission occur in HFpEF. Drp1 is a key protein regulating mitochondrial fission, and PINK1 is the upstream activator of Drp1, but their relationship with HF has not been clarified. The aim of the study is to investigate molecular mechanisms of mitochondrial dysfunctions in animals with hypertension-induced HFpEF. (2) Methods and Results: The hypertension-induced HFpEF model was established by feeding Dahl/SS rats with high salt, showing risk factors such as hypertension, mitochondrial dysfunctions, and so on. Physiological and biological measurements showed a decrease in the expression of mitochondrial function-related genes, ATP production, and mitochondrial fission index. PINK1 knockout in H9C2 cardiomyocytes showed similar effects. Moreover, PINK1 myocardium-specific overexpression activated Drp1^S616 phosphorylation and enhanced mitochondrial fission to slow the progression of hypertension-induced HFpEF. (3) Conclusions: PINK1 could phosphorylate Drp1S616 to improve mitochondrial fission and relieve mitochondrial dysfunctions, which highlights potential treatments of HFpEF. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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18 pages, 4594 KiB

Open AccessArticle

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases

by Carl-Mattheis Wahl, Constanze Schmidt, Markus Hecker and Nina D. Ullrich

Int. J. Mol. Sci. 2022, 23(17), 10174; https://doi.org/10.3390/ijms231710174 - 5 Sep 2022

Cited by 10 | Viewed by 9542

Abstract

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading [...] Read more.

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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Review

Jump to: Research

15 pages, 1407 KiB

Open AccessReview

New Insights into Cardiovascular Diseases Treatment Based on Molecular Targets

by Armanda Wojtasińska, Joanna Kućmierz, Julita Tokarek, Jill Dybiec, Anna Rodzeń, Ewelina Młynarska, Jacek Rysz and Beata Franczyk

Int. J. Mol. Sci. 2023, 24(23), 16735; https://doi.org/10.3390/ijms242316735 - 24 Nov 2023

Cited by 2 | Viewed by 2572

Abstract

Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens [...] Read more.

Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens the prognosis and becomes a therapeutic challenge. Due to the increasing number of patients with CVDs, we need to search for new risk factors and pathophysiological changes to create new strategies for preventing, diagnosing, and treating not only CVDs but also comorbidities like diabetes mellitus and lipid disorders. As increasing amount of patients suffering from CVDs, there are many therapies which focus on new molecular targets like proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3, ATP-citrate lyase, or new technologies such as siRNA in treatment of dyslipidemia or sodium-glucose co-transporter-2 and glucagon-like peptide-1 in treatment of diabetes mellitus. Both SGLT-2 inhibitors and GLP-1 receptor agonists are used in the treatment of diabetes, however, they proved to have a beneficial effect in CVDs as well. Moreover, a significant amount of evidence has shown that exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury. In our work, we would like to focus on the above mechanisms. The knowledge of them allows for the appearance of new strategies of treatment among patients with CVDs. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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20 pages, 2259 KiB

Open AccessReview

The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target

by Anna Wołowiec, Łukasz Wołowiec, Grzegorz Grześk, Albert Jaśniak, Joanna Osiak, Jakub Husejko and Mariusz Kozakiewicz

Int. J. Mol. Sci. 2023, 24(18), 13723; https://doi.org/10.3390/ijms241813723 - 6 Sep 2023

Cited by 4 | Viewed by 2263

Abstract

Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The [...] Read more.

Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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14 pages, 1279 KiB

Open AccessReview

The Role of MicroRNAs in Aortic Stenosis—Lessons from Recent Clinical Research Studies

by Anna Krauze, Grzegorz Procyk, Aleksandra Gąsecka, Izabela Garstka-Pacak and Małgorzata Wrzosek

Int. J. Mol. Sci. 2023, 24(17), 13095; https://doi.org/10.3390/ijms241713095 - 23 Aug 2023

Cited by 4 | Viewed by 1134

Abstract

Aortic stenosis (AS) is the most prevalent primary valve lesion demanding intervention. Two main treatment options are surgical aortic valve replacement or transcatheter aortic valve implantation. There is an unmet need for biomarkers that could predict treatment outcomes and become a helpful tool [...] Read more.

Aortic stenosis (AS) is the most prevalent primary valve lesion demanding intervention. Two main treatment options are surgical aortic valve replacement or transcatheter aortic valve implantation. There is an unmet need for biomarkers that could predict treatment outcomes and become a helpful tool in guiding Heart Team in the decision-making process. Micro-ribonucleic acids (microRNAs/miRs) have emerged as potential biomarkers thoroughly studied in recent years. In this review, we aimed to summarize the current knowledge about the role of miRNAs in AS based on human subject research. Much research investigating miRNAs’ role in AS has been conducted so far. We included 32 original human subject research relevant to the discussed field. Most of the presented miRNAs were studied only by a single research group. Nevertheless, several miRNAs appeared more than once, sometimes with high consistency between different studies but sometimes with apparent discrepancies. The molecular aspects of diseases are doubtlessly exciting and provide invaluable insights into the pathophysiology. Nevertheless, translating these findings, regarding biomarkers such as miRNAs, into clinical practice requires much effort, time, and further research with a focus on validating existing evidence. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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22 pages, 1107 KiB

Open AccessReview

Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure

by Fione Yip, Brian Lai and Decheng Yang

Int. J. Mol. Sci. 2023, 24(9), 7717; https://doi.org/10.3390/ijms24097717 - 23 Apr 2023

Cited by 7 | Viewed by 3059

Abstract

Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM [...] Read more.

Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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19 pages, 1353 KiB

Open AccessReview

Importance of Mitochondria in Cardiac Pathologies: Focus on Uncoupling Proteins and Monoamine Oxidases

by Rainer Schulz and Klaus-Dieter Schlüter

Int. J. Mol. Sci. 2023, 24(7), 6459; https://doi.org/10.3390/ijms24076459 - 30 Mar 2023

Cited by 15 | Viewed by 2650

Abstract

On the one hand, reactive oxygen species (ROS) are involved in the onset and progression of a wide array of diseases. On the other hand, these are a part of signaling pathways related to cell metabolism, growth and survival. While ROS are produced [...] Read more.

On the one hand, reactive oxygen species (ROS) are involved in the onset and progression of a wide array of diseases. On the other hand, these are a part of signaling pathways related to cell metabolism, growth and survival. While ROS are produced at various cellular sites, in cardiomyocytes the largest amount of ROS is generated by mitochondria. Apart from the electron transport chain and various other proteins, uncoupling protein (UCP) and monoamine oxidases (MAO) have been proposed to modify mitochondrial ROS formation. Here, we review the recent information on UCP and MAO in cardiac injuries induced by ischemia-reperfusion (I/R) as well as protection from I/R and heart failure secondary to I/R injury or pressure overload. The current data in the literature suggest that I/R will preferentially upregulate UCP2 in cardiac tissue but not UCP3. Studies addressing the consequences of such induction are currently inconclusive because the precise function of UCP2 in cardiac tissue is not well understood, and tissue- and species-specific aspects complicate the situation. In general, UCP2 may reduce oxidative stress by mild uncoupling and both UCP2 and UCP3 affect substrate utilization in cardiac tissue, thereby modifying post-ischemic remodeling. MAOs are important for the physiological regulation of substrate concentrations. Upon increased expression and or activity of MAOs, however, the increased production of ROS and reactive aldehydes contribute to cardiac alterations such as hypertrophy, inflammation, irreversible cardiomyocyte injury, and failure. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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13 pages, 617 KiB

Open AccessReview

Recent Advances in Generation of In Vitro Cardiac Organoids

by Makoto Sahara

Int. J. Mol. Sci. 2023, 24(7), 6244; https://doi.org/10.3390/ijms24076244 - 26 Mar 2023

Cited by 13 | Viewed by 4533

Abstract

Cardiac organoids are in vitro self-organizing and three-dimensional structures composed of multiple cardiac cells (i.e., cardiomyocytes, endothelial cells, cardiac fibroblasts, etc.) with or without biological scaffolds. Since cardiac organoids recapitulate structural and functional characteristics of the native heart to a higher degree compared [...] Read more.

Cardiac organoids are in vitro self-organizing and three-dimensional structures composed of multiple cardiac cells (i.e., cardiomyocytes, endothelial cells, cardiac fibroblasts, etc.) with or without biological scaffolds. Since cardiac organoids recapitulate structural and functional characteristics of the native heart to a higher degree compared to the conventional two-dimensional culture systems, their applications, in combination with pluripotent stem cell technologies, are being widely expanded for the investigation of cardiogenesis, cardiac disease modeling, drug screening and development, and regenerative medicine. In this mini-review, recent advances in cardiac organoid technologies are summarized in chronological order, with a focus on the methodological points for each organoid formation. Further, the current limitations and the future perspectives in these promising systems are also discussed. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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13 pages, 1029 KiB

Open AccessReview

Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus

by Jelena Rakocevic, Milan Dobric, Rada Vucic, Matija Furtula, Ivan Zaletel, Katarina Milutinovic, Ana Ilijevski, Milica Labudovic Borovic, Miloje Tomasevic and Milos Bajcetic

Int. J. Mol. Sci. 2023, 24(6), 6012; https://doi.org/10.3390/ijms24066012 - 22 Mar 2023

Cited by 1 | Viewed by 3036

Abstract

The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and [...] Read more.

The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and persistent effects on lowering the LDL cholesterol level, while reducing the risk of future cardiovascular events. However, this therapy requires once- or twice-monthly administration in the form of subcutaneous injection. This dosing regimen might impact the therapy adherence in cardiovascular patients who often require multiple drugs with different dosing intervals. Small interfering ribonucleic acid (siRNA) represents a promising therapy approach for patients with elevated LDL cholesterol level despite optimized background statin therapy. Inclisiran is a synthesized siRNA which inhibits PCSK9 synthesis in the liver and provides sustained and durable lowering of LDL cholesterol with twice-yearly application and a good tolerability profile. Herein, we present an overview of the current available data and critical review of the major clinical trials which assessed safety and efficacy of inclisiran in different groups of patients with elevated LDL cholesterol level. Full article

(This article belongs to the Special Issue New Insights into Cardiovascular Diseases in Basic Research)

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