International Journal of Molecular Sciences

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18 pages, 2892 KiB

Open AccessArticle

Pericardial Fluid Accumulates microRNAs That Regulate Heart Fibrosis after Myocardial Infarction

by Elsa D. Silva, Daniel Pereira-Sousa, Francisco Ribeiro-Costa, Rui Cerqueira, Francisco J. Enguita, Rita N. Gomes, João Dias-Ferreira, Cassilda Pereira, Ana Castanheira, Perpétua Pinto-do-Ó, Adelino F. Leite-Moreira and Diana S. Nascimento

Int. J. Mol. Sci. 2024, 25(15), 8329; https://doi.org/10.3390/ijms25158329 - 30 Jul 2024

Viewed by 1192

Abstract

Pericardial fluid (PF) has been suggested as a reservoir of molecular targets that can be modulated for efficient repair after myocardial infarction (MI). Here, we set out to address the content of this biofluid after MI, namely in terms of microRNAs (miRs) that [...] Read more.

Pericardial fluid (PF) has been suggested as a reservoir of molecular targets that can be modulated for efficient repair after myocardial infarction (MI). Here, we set out to address the content of this biofluid after MI, namely in terms of microRNAs (miRs) that are important modulators of the cardiac pathological response. PF was collected during coronary artery bypass grafting (CABG) from two MI cohorts, patients with non-ST-segment elevation MI (NSTEMI) and patients with ST-segment elevation MI (STEMI), and a control group composed of patients with stable angina and without previous history of MI. The PF miR content was analyzed by small RNA sequencing, and its biological effect was assessed on human cardiac fibroblasts. PF accumulates fibrotic and inflammatory molecules in STEMI patients, namely causing the soluble suppression of tumorigenicity 2 (ST-2), which inversely correlates with the left ventricle ejection fraction. Although the PF of the three patient groups induce similar levels of fibroblast-to-myofibroblast activation in vitro, RNA sequencing revealed that PF from STEMI patients is particularly enriched not only in pro-fibrotic miRs but also anti-fibrotic miRs. Among those, miR-22-3p was herein found to inhibit TGF-β-induced human cardiac fibroblast activation in vitro. PF constitutes an attractive source for screening diagnostic/prognostic miRs and for unveiling novel therapeutic targets in cardiac fibrosis. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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14 pages, 913 KiB

Open AccessArticle

Proteomic Profiling of Endothelial Cells Exposed to Mitomycin C: Key Proteins and Pathways Underlying Genotoxic Stress-Induced Endothelial Dysfunction

by Maxim Sinitsky, Egor Repkin, Anna Sinitskaya, Victoria Markova, Daria Shishkova and Olga Barbarash

Int. J. Mol. Sci. 2024, 25(7), 4044; https://doi.org/10.3390/ijms25074044 - 5 Apr 2024

Viewed by 1462

Abstract

Mitomycin C (MMC)-induced genotoxic stress can be considered to be a novel trigger of endothelial dysfunction and atherosclerosis—a leading cause of cardiovascular morbidity and mortality worldwide. Given the increasing genotoxic load on the human organism, the decryption of the molecular pathways underlying genotoxic [...] Read more.

Mitomycin C (MMC)-induced genotoxic stress can be considered to be a novel trigger of endothelial dysfunction and atherosclerosis—a leading cause of cardiovascular morbidity and mortality worldwide. Given the increasing genotoxic load on the human organism, the decryption of the molecular pathways underlying genotoxic stress-induced endothelial dysfunction could improve our understanding of the role of genotoxic stress in atherogenesis. Here, we performed a proteomic profiling of human coronary artery endothelial cells (HCAECs) and human internal thoracic endothelial cells (HITAECs) in vitro that were exposed to MMC to identify the biochemical pathways and proteins underlying genotoxic stress-induced endothelial dysfunction. We denoted 198 and 71 unique, differentially expressed proteins (DEPs) in the MMC-treated HCAECs and HITAECs, respectively; only 4 DEPs were identified in both the HCAECs and HITAECs. In the MMC-treated HCAECs, 44.5% of the DEPs were upregulated and 55.5% of the DEPs were downregulated, while in HITAECs, these percentages were 72% and 28%, respectively. The denoted DEPs are involved in the processes of nucleotides and RNA metabolism, vesicle-mediated transport, post-translation protein modification, cell cycle control, the transport of small molecules, transcription and signal transduction. The obtained results could improve our understanding of the fundamental basis of atherogenesis and help in the justification of genotoxic stress as a risk factor for atherosclerosis. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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9 pages, 467 KiB

Open AccessCommunication

Lack of Association between Serum Chitotriosidase Activity and Arterial Stiffness in Type 2 Diabetes without Cardiovascular Complications

by Luca D’Onofrio, Rocco Amendolara, Carmen Mignogna, Gaetano Leto, Lida Tartaglione, Sandro Mazzaferro, Ernesto Maddaloni and Raffaella Buzzetti

Int. J. Mol. Sci. 2023, 24(21), 15809; https://doi.org/10.3390/ijms242115809 - 31 Oct 2023

Cited by 1 | Viewed by 1072

Abstract

Chitotriosidase (CHIT), a mammalian chitinase secreted by neutrophils and activated macrophages, is increased in both cardiovascular disease (CVD) and type 2 diabetes (T2D). Arterial stiffness rises early in T2D and increases the risk of CVD. The aim of this study is to evaluate [...] Read more.

Chitotriosidase (CHIT), a mammalian chitinase secreted by neutrophils and activated macrophages, is increased in both cardiovascular disease (CVD) and type 2 diabetes (T2D). Arterial stiffness rises early in T2D and increases the risk of CVD. The aim of this study is to evaluate CHIT activity as an early biomarker of arterial stiffness in people with T2D free from overt vascular complications. In this cross-sectional study, arterial stiffness as measured using standard pulse wave velocity (PWV) was evaluated in 174 people with T2D without overt vascular disease. Then, we measured CHIT serum activity with an electrochemiluminescence assay in two subgroups of participants: 35 with the highest (high-PWV) and 40 with the lowest (low-PWV) PWV values. CHIT activity was no different between the low-PVW and high-PWV groups (12.7 [9.6–17.9] vs. 11.4 [8.8–15.0] nmol/mL/h, respectively). Compared with the low-PWV group, the high-PWV participants were older (p < 0.001); had a longer duration of diabetes (p = 0.03); higher ankle–brachial index ABI (p = 0.04), systolic blood pressure (p = 0.002), diastolic blood pressure (p = 0.005), fasting blood glucose (p = 0.008), and HbA1c (p = 0.005); and lower eGFR (p = 0.03) and body mass index (BMI) (p = 0.01). No association was present with sex, duration of diabetes, age, BMI, peripheral blood pressure, laboratory parameters, and glucose-lowering medications or ongoing antihypertensive therapy. Although no association was found, this study provides novel data about the association of CHIT activity with CVD, focusing on a specific outcome (arterial stiffness) in a well-defined population of subjects with T2D without established CVD. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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19 pages, 4611 KiB

Open AccessArticle

Doxorubicin-Induced Cardiomyopathy: A Preliminary Study on the Cardioprotective Benefits of 7-Hydroxyflavanone

by Nonhlakanipho F. Sangweni, Kwazi Gabuza, Ruzayda van Aarde, Lawrence Mabasa, Derick van Vuuren, Barbara Huisamen, Reenen Barry and Rabia Johnson

Int. J. Mol. Sci. 2023, 24(20), 15395; https://doi.org/10.3390/ijms242015395 - 20 Oct 2023

Viewed by 1361

Abstract

The therapeutic properties of flavonoids are reported to offer cardioprotective benefits against doxorubicin (Dox)-induced cardiotoxicity (DIC). In the current study, we aimed to investigate the prophylactic properties of 7-hydroxyflavanone (7H), a flavonoid with antioxidative properties, against DIC. An in vitro model of DIC [...] Read more.

The therapeutic properties of flavonoids are reported to offer cardioprotective benefits against doxorubicin (Dox)-induced cardiotoxicity (DIC). In the current study, we aimed to investigate the prophylactic properties of 7-hydroxyflavanone (7H), a flavonoid with antioxidative properties, against DIC. An in vitro model of DIC was established by exposing H9c2 cardiomyoblasts to Dox for 6 days. Similarly, cells were also co-treated with 7H to assess its ability to mitigate DIC. The data obtained indicate that 7H, as a co-treatment, alleviates Dox-induced oxidative stress by enhancing total glutathione content (p ≤ 0.001) and superoxide dismutase activity (p ≤ 0.001) whilst decreasing ROS (p ≤ 0.001), malondialdehyde production (p ≤ 0.001) and the secretion of interleukin-6 (p ≤ 0.001). The data also showed an improvement in mitochondrial function as shown via enhanced bioenergetics, mitochondrial membrane potential, and PGC1-alpha (p ≤ 0.05) and pAMPK (p ≤ 0.001) expression. The cardioprotective potential of 7H was further highlighted by its ability attenuate Dox-induced caspase 3/7 activity (p ≤ 0.001), apoptosis (p ≤ 0.001) and necrosis (p ≤ 0.05). In conclusion, our findings demonstrated the cardioprotective benefits of 7H and thus suggests that it could be a suitable candidate cardioprotective agent against DIC. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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18 pages, 8319 KiB

Open AccessArticle

miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy

by Sonia Terriaca, Maria Giovanna Scioli, Calogera Pisano, Giovanni Ruvolo, Amedeo Ferlosio and Augusto Orlandi

Int. J. Mol. Sci. 2023, 24(20), 15133; https://doi.org/10.3390/ijms242015133 - 13 Oct 2023

Cited by 4 | Viewed by 1508

Abstract

Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. [...] Read more.

Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. We previously reported miR-632 upregulation in MFS TAA tissues compared with non-genetic TAA tissues. DNAJB6 is a gene target of miR-632 in cancer and plays a critical role in blocking epithelial-to-mesenchymal transition by inhibiting the Wnt/β catenin pathway. TGF-β signaling also activates Wnt/β catenin signaling and induces endothelial-to-mesenchymal transition (End-Mt) and fibrosis. We documented that miR-632 upregulation correlated with DNAJB6 expression in both the endothelium and the tunica media of MFS TAA (p < 0.01). Wnt/β catenin signaling, End-Mt, and fibrosis markers were also upregulated in MFS TAA tissues (p < 0.05, p < 0.01 and p < 0.001). Moreover, miR-632 overexpression inhibited DNAJB6, inducing Wnt/β catenin signaling, as well as End-Mt and fibrosis exacerbation (p < 0.05 and p < 0.01). TGF-β1 treatment also determined miR-632 upregulation (p < 0.01 and p < 0.001), with the consequent activation of the aforementioned processes. Our study provides new insights about the pathogenetic mechanisms in MFS aortopathy. Moreover, the high disease specificity of miR-632 and DNAJB6 suggests new potential prognostic factors and/or therapeutic targets in the progression of MFS aortopathy. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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9 pages, 2196 KiB

Open AccessCommunication

Systemic Effects of Homoarginine Supplementation on Arginine Metabolizing Enzymes in Rats with Heart Failure with Preserved Ejection Fraction

by Petra Büttner, Sarah Werner, Julia Böttner, Susann Ossmann, Edzard Schwedhelm and Holger Thiele

Int. J. Mol. Sci. 2023, 24(19), 14782; https://doi.org/10.3390/ijms241914782 - 30 Sep 2023

Cited by 1 | Viewed by 1225

Abstract

A restoration of low homoarginine (hArg) levels in obese ZSF1 rats (O-ZSF1) before (S1-ZSF1) and after (S2-ZSF1) the manifestation of heart failure with preserved ejection fraction (HFpEF) did not affect the worsening of cardiac HFpEF characteristics. Here, potential regulation of key enzymes of [...] Read more.

A restoration of low homoarginine (hArg) levels in obese ZSF1 rats (O-ZSF1) before (S1-ZSF1) and after (S2-ZSF1) the manifestation of heart failure with preserved ejection fraction (HFpEF) did not affect the worsening of cardiac HFpEF characteristics. Here, potential regulation of key enzymes of arginine metabolism in other organs was analyzed. Arginase 2 (ARG2) was reduced >35% in the kidney and small intestine of hArg-supplemented rats compared to O-ZSF1. Glycine amidinotransferase (GATM) was 29% upregulated in the kidneys of S1-ZSF1. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) levels were reduced >50% in the livers of O-ZSF1 but restored in S2-ZSF1 compared to healthy rats (L-ZSF1). In the skeletal muscle, iNOS was lower in O-ZSF1 and further decreased in S1-ZSF1 and S2-ZSF1 compared to L-ZSF1. iNOS levels were lower in the liver of the S2-ZSF1 group but higher in the kidneys of S1-ZSF1 compared to L-ZSF1. Supplementation with hArg in an in vivo HFpEF model resulted in the inhibition of renal ARG2 and an increase in GATM expression. This supplementation might contribute to the stabilization of intestinal iNOS and ARG2 imbalances, thereby enhancing barrier function. Additionally, it may offer protective effects in skeletal muscle by downregulating iNOS. In the conceptualization of hArg supplementation studies, the current disease progression stage as well as organ-specific enzyme regulation should be considered. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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16 pages, 6891 KiB

Open AccessArticle

mTOR Inhibitors Modulate the Physical Properties of 3D Spheroids Derived from H9c2 Cells

by Megumi Watanabe, Toshiyuki Yano, Tatsuya Sato, Araya Umetsu, Megumi Higashide, Masato Furuhashi and Hiroshi Ohguro

Int. J. Mol. Sci. 2023, 24(14), 11459; https://doi.org/10.3390/ijms241411459 - 14 Jul 2023

Cited by 5 | Viewed by 1774

Abstract

To establish an appropriate in vitro model for the local environment of cardiomyocytes, three-dimensional (3D) spheroids derived from H9c2 cardiomyoblasts were prepared, and their morphological, biophysical phase contrast and biochemical characteristics were evaluated. The 3D H9c2 spheroids were successfully obtained, the sizes of [...] Read more.

To establish an appropriate in vitro model for the local environment of cardiomyocytes, three-dimensional (3D) spheroids derived from H9c2 cardiomyoblasts were prepared, and their morphological, biophysical phase contrast and biochemical characteristics were evaluated. The 3D H9c2 spheroids were successfully obtained, the sizes of the spheroids decreased, and they became stiffer during 3–4 days. In contrast to the cell multiplication that occurs in conventional 2D planar cell cultures, the 3D H9c2 spheroids developed into a more mature form without any cell multiplication being detected. qPCR analyses of the 3D H9c2 spheroids indicated that the production of collagen4 (COL4) and fibronectin (FN), connexin43 (CX43), β-catenin, N-cadherin, STAT3, and HIF1 molecules had increased and that the production of COL6 and α-smooth muscle actin (α-SMA) molecules had decreased as compared to 2D cultured cells. In addition, treatment with rapamycin (Rapa), an mTOR complex (mTORC) 1 inhibitor, and Torin 1, an mTORC1/2 inhibitor, resulted in significantly decreased cell densities of the 2D cultured H9c2 cells, but the size and stiffness of the H9c2 cells within the 3D spheroids were reduced with the gene expressions of several of the above several factors being reduced. The metabolic responses to mTOR modulators were also different between the 2D and 3D cultures. These results suggest that as unique aspects of the local environments of the 3D spheroids, the spontaneous expression of GJ-related molecules and hypoxia within the core may be associated with their maturation, suggesting that this may become a useful in vitro model that replicates the local environment of cardiomyocytes. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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18 pages, 5569 KiB

Open AccessArticle

Lamin A/C Ablation Restricted to Vascular Smooth Muscle Cells, Cardiomyocytes, and Cardiac Fibroblasts Causes Cardiac and Vascular Dysfunction

by Alberto Del Monte-Monge, Íñigo Ruiz-Polo de Lara, Pilar Gonzalo, Carla Espinós-Estévez, María González-Amor, Miguel de la Fuente-Pérez, María J. Andrés-Manzano, Víctor Fanjul, Juan R. Gimeno, Roberto Barriales-Villa, Beatriz Dorado and Vicente Andrés

Int. J. Mol. Sci. 2023, 24(13), 11172; https://doi.org/10.3390/ijms241311172 - 6 Jul 2023

Viewed by 2252

Abstract

Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human [...] Read more.

Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through which LMNA mutations provoke cardiac alterations, with a particular focus on cardiomyocytes. To investigate if LMNA mutations also cause vascular alterations that might contribute to the etiopathogenesis of LMNA-DCM, we generated and characterized Lmna^flox/floxSM22αCre mice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation, Lmna^flox/floxSM22αCre mice recapitulated the main hallmarks of human LMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with elevated expression of total and phosphorylated (active) Smad3 and cleaved (active) caspase 3 in the heart. Lmna^flox/floxSM22αCre mice also exhibited perivascular fibrosis in the coronary arteries and a switch of aortic VSMCs from the ‘contractile’ to the ‘synthetic’ phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents in Lmna^flox/floxSM22αCre mice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms of LMNA-DCM. Future work addressing the mechanisms underlying vascular defects in LMNA-DCM may open new therapeutic avenues for these diseases. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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23 pages, 8664 KiB

Open AccessArticle

Myokine Musclin Is Critical for Exercise-Induced Cardiac Conditioning

by Matthew P. Harris, Shemin Zeng, Zhiyong Zhu, Vitor A. Lira, Liping Yu, Denice M. Hodgson-Zingman and Leonid V. Zingman

Int. J. Mol. Sci. 2023, 24(7), 6525; https://doi.org/10.3390/ijms24076525 - 30 Mar 2023

Cited by 8 | Viewed by 3284

Abstract

This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce [...] Read more.

This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce and secrete myokines, which mediate local and systemic “crosstalk” to promote exercise tolerance and overall health, including cardiac conditioning. The myokine musclin, highly conserved across animal species, has been shown to be upregulated in response to physical activity. However, musclin effects on exercise-induced cardiac conditioning are not established. Following completion of a treadmill exercise protocol, wild type (WT) mice and mice with disruption of the musclin-encoding gene, Ostn, had their hearts extracted and exposed to an ex vivo ischemia-reperfusion protocol or biochemical studies. Disruption of musclin signaling abolished the ability of exercise to mitigate cardiac ischemic injury. This impaired cardioprotection was associated with reduced mitochondrial content and function linked to blunted cyclic guanosine monophosphate (cGMP) signaling. Genetic deletion of musclin reduced the nuclear abundance of protein kinase G (PKGI) and cyclic adenosine monophosphate (cAMP) response element binding (CREB), resulting in suppression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and its downstream targets in response to physical activity. Synthetic musclin peptide pharmacokinetic parameters were defined and used to calculate the infusion rate necessary to maintain its plasma level comparable to that observed after exercise. This infusion was found to reproduce the cardioprotective benefits of exercise in sedentary WT and Ostn-KO mice. Musclin is essential for exercise-induced cardiac protection. Boosting musclin signaling might serve as a novel therapeutic strategy for cardioprotection. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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Review

Jump to: Research

20 pages, 615 KiB

Open AccessReview

Clinical Significance of B-Type Natriuretic Peptide and N-Terminal Pro-B-Type Natriuretic Peptide in Pediatric Patients: Insights into Their Utility in the Presence or Absence of Pre-Existing Heart Conditions

by Kamila Maria Ludwikowska, Monika Tokarczyk, Bartłomiej Paleczny, Paweł Tracewski, Leszek Szenborn and Jacek Kusa

Int. J. Mol. Sci. 2024, 25(16), 8781; https://doi.org/10.3390/ijms25168781 - 12 Aug 2024

Viewed by 1136

Abstract

The clinical significance of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients remains an area of evolving understanding, particularly regarding their utility in the presence or absence of pre-existing heart conditions. While clear cutoff values and established roles [...] Read more.

The clinical significance of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients remains an area of evolving understanding, particularly regarding their utility in the presence or absence of pre-existing heart conditions. While clear cutoff values and established roles in heart failure are understood in adult patients, pediatric norms vary with age, complicating interpretation. Notably, the emergence of multi-system inflammatory syndrome in children (MIS-C) has highlighted the importance of these markers not only in the detection of acute heart failure but also as a marker of disease severity and even as a differential diagnosis tool. This review summarizes current knowledge on the utility of BNP and NT-proBNP in pediatric patients. Their unique physiology, including circulation and compensation mechanisms, likely influence BNP and NT-proBNP release, potentially even in non-heart failure states. Factors such as dynamic volemic changes accompanying inflammatory diseases in children may contribute. Thus, understanding the nuanced roles of BNP and NT-proBNP in pediatric populations is crucial for the accurate diagnosis, management, and differentiation of cardiac and non-cardiac conditions. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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20 pages, 1447 KiB

Open AccessReview

Sex-Based Mechanisms of Cardiac Development and Function: Applications for Induced-Pluripotent Stem Cell Derived-Cardiomyocytes

by Yinhan Luo, Sina Safabakhsh, Alessia Palumbo, Céline Fiset, Carol Shen, Jeremy Parker, Leonard J. Foster and Zachary Laksman

Int. J. Mol. Sci. 2024, 25(11), 5964; https://doi.org/10.3390/ijms25115964 - 29 May 2024

Viewed by 1301

Abstract

Males and females exhibit intrinsic differences in the structure and function of the heart, while the prevalence and severity of cardiovascular disease vary in the two sexes. However, the mechanisms of this sex-based dimorphism are yet to be elucidated. Sex chromosomes and sex [...] Read more.

Males and females exhibit intrinsic differences in the structure and function of the heart, while the prevalence and severity of cardiovascular disease vary in the two sexes. However, the mechanisms of this sex-based dimorphism are yet to be elucidated. Sex chromosomes and sex hormones are the main contributors to sex-based differences in cardiac physiology and pathophysiology. In recent years, the advances in induced pluripotent stem cell-derived cardiac models and multi-omic approaches have enabled a more comprehensive understanding of the sex-specific differences in the human heart. Here, we provide an overview of the roles of these two factors throughout cardiac development and explore the sex hormone signaling pathways involved. We will also discuss how the employment of stem cell-based cardiac models and single-cell RNA sequencing help us further investigate sex differences in healthy and diseased hearts. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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17 pages, 1081 KiB

Open AccessReview

The Role of Inflammasome in Abdominal Aortic Aneurysm and Its Potential Drugs

by Suyu Pi, Sizheng Xiong, Yan Yuan and Hongping Deng

Int. J. Mol. Sci. 2024, 25(9), 5001; https://doi.org/10.3390/ijms25095001 - 3 May 2024

Viewed by 1443

Abstract

Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year [...] Read more.

Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic inflammatory response is the core process in AAA occurrence and development. Inflammasome, a multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory cytokines like interleukin (IL)-1β and IL-18, and thus plays a pivotal role in inflammation regulation. Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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25 pages, 3998 KiB

Open AccessReview

Use of Statins in Heart Failure with Preserved Ejection Fraction: Current Evidence and Perspectives

by Artem Ovchinnikov, Alexandra Potekhina, Tatiana Arefieva, Anastasiia Filatova, Fail Ageev and Evgeny Belyavskiy

Int. J. Mol. Sci. 2024, 25(9), 4958; https://doi.org/10.3390/ijms25094958 - 1 May 2024

Cited by 1 | Viewed by 2598

Abstract

Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and [...] Read more.

Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and may be beneficial in HF, especially in HFpEF. Numerous observational clinical trials have consistently shown a beneficial prognostic effect of statins in patients with HFpEF, while the results of two larger trials in patients with HFrEF have been controversial. Such differences may be related to a more pronounced impact of the pleiotropic properties of statins on the pathophysiology of HFpEF and pro-inflammatory comorbidities (arterial hypertension, diabetes mellitus, obesity, chronic kidney disease) that are more common in HFpEF. This review discusses the potential mechanisms of statin action that may be beneficial for patients with HFpEF, as well as clinical trials that have evaluated the statin effects on left ventricular diastolic function and clinical outcomes in patients with HFpEF. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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25 pages, 3220 KiB

Open AccessReview

Photodynamic Therapy for Atherosclerosis

by Wiktoria Mytych, Dorota Bartusik-Aebisher, Aleksandra Łoś, Klaudia Dynarowicz, Angelika Myśliwiec and David Aebisher

Int. J. Mol. Sci. 2024, 25(4), 1958; https://doi.org/10.3390/ijms25041958 - 6 Feb 2024

Cited by 4 | Viewed by 2994

Abstract

Atherosclerosis, which currently contributes to 31% of deaths globally, is of critical cardiovascular concern. Current diagnostic tools and biomarkers are limited, emphasizing the need for early detection. Lifestyle modifications and medications form the basis of treatment, and emerging therapies such as photodynamic therapy [...] Read more.

Atherosclerosis, which currently contributes to 31% of deaths globally, is of critical cardiovascular concern. Current diagnostic tools and biomarkers are limited, emphasizing the need for early detection. Lifestyle modifications and medications form the basis of treatment, and emerging therapies such as photodynamic therapy are being developed. Photodynamic therapy involves a photosensitizer selectively targeting components of atherosclerotic plaques. When activated by specific light wavelengths, it induces localized oxidative stress aiming to stabilize plaques and reduce inflammation. The key advantage lies in its selective targeting, sparing healthy tissues. While preclinical studies are encouraging, ongoing research and clinical trials are crucial for optimizing protocols and ensuring long-term safety and efficacy. The potential combination with other therapies makes photodynamic therapy a versatile and promising avenue for addressing atherosclerosis and associated cardiovascular disease. The investigations underscore the possibility of utilizing photodynamic therapy as a valuable treatment choice for atherosclerosis. As advancements in research continue, photodynamic therapy might become more seamlessly incorporated into clinical approaches for managing atherosclerosis, providing a blend of efficacy and limited invasiveness. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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29 pages, 786 KiB

Open AccessReview

Current Medical Therapy and Revascularization in Peripheral Artery Disease of the Lower Limbs: Impacts on Subclinical Chronic Inflammation

by Andrea Leonardo Cecchini, Federico Biscetti, Matteo Manzato, Lorenzo Lo Sasso, Maria Margherita Rando, Maria Anna Nicolazzi, Enrica Rossini, Luis H. Eraso, Paul J. Dimuzio, Massimo Massetti, Antonio Gasbarrini and Andrea Flex

Int. J. Mol. Sci. 2023, 24(22), 16099; https://doi.org/10.3390/ijms242216099 - 8 Nov 2023

Cited by 2 | Viewed by 2682

Abstract

Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. This paper aims to conduct a literature review on pharmacotherapy for PAD, specifically focusing on how different drug classes target pro-inflammatory [...] Read more.

Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. This paper aims to conduct a literature review on pharmacotherapy for PAD, specifically focusing on how different drug classes target pro-inflammatory pathways. The goal is to enhance the choice of therapeutic plans by considering their impact on the chronic subclinical inflammation that is associated with PAD development and progression. We conducted a comprehensive review of currently published original articles, narratives, systematic reviews, and meta-analyses. The aim was to explore the relationship between PAD and inflammation and evaluate the influence of current pharmacological and nonpharmacological interventions on the underlying chronic subclinical inflammation. Our findings indicate that the existing treatments have added anti-inflammatory properties that can potentially delay or prevent PAD progression and improve outcomes, independent of their effects on traditional risk factors. Although inflammation-targeted therapy in PAD shows promising potential, its benefits have not been definitively proven yet. However, it is crucial not to overlook the pleiotropic properties of the currently available treatments, as they may provide valuable insights for therapeutic strategies. Further studies focusing on the anti-inflammatory and immunomodulatory effects of these treatments could enhance our understanding of the mechanisms contributing to the residual risk in PAD and pave the way for the development of novel therapies. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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14 pages, 972 KiB

Open AccessReview

Myocardial Fibrosis in Hypertrophic Cardiomyopathy: A Perspective from Fibroblasts

by Maja Schlittler, Peter P. Pramstaller, Alessandra Rossini and Marzia De Bortoli

Int. J. Mol. Sci. 2023, 24(19), 14845; https://doi.org/10.3390/ijms241914845 - 2 Oct 2023

Cited by 7 | Viewed by 3268

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and the leading cause of sudden cardiac death in young people. Mutations in genes that encode structural proteins of the cardiac sarcomere are the more frequent genetic cause of HCM. The disease is [...] Read more.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and the leading cause of sudden cardiac death in young people. Mutations in genes that encode structural proteins of the cardiac sarcomere are the more frequent genetic cause of HCM. The disease is characterized by cardiomyocyte hypertrophy and myocardial fibrosis, which is defined as the excessive deposition of extracellular matrix proteins, mainly collagen I and III, in the myocardium. The development of fibrotic tissue in the heart adversely affects cardiac function. In this review, we discuss the latest evidence on how cardiac fibrosis is promoted, the role of cardiac fibroblasts, their interaction with cardiomyocytes, and their activation via the TGF-β pathway, the primary intracellular signalling pathway regulating extracellular matrix turnover. Finally, we summarize new findings on profibrotic genes as well as genetic and non-genetic factors involved in the pathophysiology of HCM. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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17 pages, 2341 KiB

Open AccessReview

Electrical and Structural Insights into Right Ventricular Outflow Tract Arrhythmogenesis

by Yen-Yu Lu, Yao-Chang Chen, Yung-Kuo Lin, Shih-Ann Chen and Yi-Jen Chen

Int. J. Mol. Sci. 2023, 24(14), 11795; https://doi.org/10.3390/ijms241411795 - 22 Jul 2023

Cited by 4 | Viewed by 2250

Abstract

The right ventricular outflow tract (RVOT) is the major origin of ventricular arrhythmias, including premature ventricular contractions, idiopathic ventricular arrhythmias, Brugada syndrome, torsade de pointes, long QT syndrome, and arrhythmogenic right ventricular cardiomyopathy. The RVOT has distinct developmental origins and cellular characteristics and [...] Read more.

The right ventricular outflow tract (RVOT) is the major origin of ventricular arrhythmias, including premature ventricular contractions, idiopathic ventricular arrhythmias, Brugada syndrome, torsade de pointes, long QT syndrome, and arrhythmogenic right ventricular cardiomyopathy. The RVOT has distinct developmental origins and cellular characteristics and a complex myocardial architecture with high shear wall stress, which may lead to its high vulnerability to arrhythmogenesis. RVOT myocytes are vulnerable to intracellular sodium and calcium overload due to calcium handling protein modulation, enhanced CaMKII activity, ryanodine receptor phosphorylation, and a higher cAMP level activated by predisposing factors or pathological conditions. A reduction in Cx43 and Scn5a expression may lead to electrical uncoupling in RVOT. The purpose of this review is to update the current understanding of the cellular and molecular mechanisms of RVOT arrhythmogenesis. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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16 pages, 2252 KiB

Open AccessReview

The Role of Galectin-3 in Predicting Congenital Heart Disease Outcome: A Review of the Literature

by Amalia Făgărășan, Maria Săsăran, Liliana Gozar, Andrei Crauciuc and Claudia Bănescu

Int. J. Mol. Sci. 2023, 24(13), 10511; https://doi.org/10.3390/ijms241310511 - 22 Jun 2023

Cited by 4 | Viewed by 1897

Abstract

Galectin-3 (Gal-3) is a novel pro-fibrotic biomarker that can predict both right and left cardiac dysfunction caused by various cardiovascular conditions. Its expression seems to be progressively altered with evolving cardiac remodeling processes, even before the onset of heart failure. Hence, Gal-3 has [...] Read more.

Galectin-3 (Gal-3) is a novel pro-fibrotic biomarker that can predict both right and left cardiac dysfunction caused by various cardiovascular conditions. Its expression seems to be progressively altered with evolving cardiac remodeling processes, even before the onset of heart failure. Hence, Gal-3 has been found to be an individual predictor of acute and chronic heart failure or to serve as part of an integrated biomarker panel that can foresee adverse cardiac outcomes. In congenital heart disease (CHD), Gal-3 correlates with cardiac mortality and complications in both children and adults and is proposed as a therapeutic target in order to reverse the activation of pro-fibrosis pathways that lead to heart failure. Positive associations between serum Gal-3 levels, post-operatory hospitalization rates, complications and ventricular dysfunction have also been reported within studies conducted on patients with CHD who underwent corrective surgery. Thus, this review tried to address the potential utility of Gal-3 in patients with CHD and particularly in those who undergo corrective surgery. The heterogeneity of the literature data and the lack of validation of the results obtained by the current studies on larger cohorts cannot be neglected, though. Further longitudinal research is required to establish how Gal-3 can relate to long-term outcomes in pediatric CHD. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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16 pages, 966 KiB

Open AccessReview

Target and Cell Therapy for Atherosclerosis and CVD

by Yuliya V. Markina, Tatiana V. Kirichenko, Taisiya V. Tolstik, Anastasia I. Bogatyreva, Ulyana S. Zotova, Vadim R. Cherednichenko, Anton Yu. Postnov and Alexander M. Markin

Int. J. Mol. Sci. 2023, 24(12), 10308; https://doi.org/10.3390/ijms241210308 - 18 Jun 2023

Cited by 5 | Viewed by 2480

Abstract

Cardiovascular diseases (CVD) and, in particular, atherosclerosis, remain the main cause of death in the world today. Unfortunately, in most cases, CVD therapy begins after the onset of clinical symptoms and is aimed at eliminating them. In this regard, early pathogenetic therapy for [...] Read more.

Cardiovascular diseases (CVD) and, in particular, atherosclerosis, remain the main cause of death in the world today. Unfortunately, in most cases, CVD therapy begins after the onset of clinical symptoms and is aimed at eliminating them. In this regard, early pathogenetic therapy for CVD remains an urgent problem in modern science and healthcare. Cell therapy, aimed at eliminating tissue damage underlying the pathogenesis of some pathologies, including CVD, by replacing it with various cells, is of the greatest interest. Currently, cell therapy is the most actively developed and potentially the most effective treatment strategy for CVD associated with atherosclerosis. However, this type of therapy has some limitations. In this review, we have tried to summarize the main targets of cell therapy for CVD and atherosclerosis in particular based on the analysis using the PubMed and Scopus databases up to May 2023. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Molecular Mechanisms and Potential Therapy)

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