International Journal of Molecular Sciences

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15 pages, 7838 KiB

Open AccessArticle

Reduced Levels of Selenium and Thioredoxin Reductase in the Thoracic Aorta Could Contribute to Aneurysm Formation in Patients with Marfan Syndrome

by María Elena Soto, Israel Pérez-Torres, Linaloe Manzano-Pech, Elizabeth Soria-Castro, Almilcar Morales-Marín, Edgar Samuel Ramírez-Marroquín, Humberto Martínez-Hernández, Valentín Herrera-Alarcón and Verónica Guarner-Lans

Int. J. Mol. Sci. 2023, 24(13), 10429; https://doi.org/10.3390/ijms241310429 - 21 Jun 2023

Cited by 1 | Viewed by 1440

Abstract

Marfan syndrome (MFS) is an autosomal dominant disorder caused by a heterozygous mutation of the FBN1 gene. MFS patients present oxidative stress that disturbs redox homeostasis. Redox homeostasis depends in part on the enzymatic antioxidant system, which includes thioredoxin reductase (TrxR) and glutathione [...] Read more.

Marfan syndrome (MFS) is an autosomal dominant disorder caused by a heterozygous mutation of the FBN1 gene. MFS patients present oxidative stress that disturbs redox homeostasis. Redox homeostasis depends in part on the enzymatic antioxidant system, which includes thioredoxin reductase (TrxR) and glutathione peroxidases (GPx), both of which require an adequate concentration of selenium (Se). Therefore, the aim of this study was to determine if Se levels are decreased in the TAA of patients with MFS since this could contribute to the formation of an aneurysm in these patients. The results show that interleukins IL-1β, IL-6 TGF-β1, and TNF-α (p ≤ 0.03), and carbonylation (p ≤ 0.03) were increased in the TAA of patients with MFS in comparison with control subjects, while Se, thiols (p = 0.02), TrxR, and GPx (p ≤ 0.001) were decreased. TLR4 and NOX1 (p ≤ 0.03), MMP9 and MMP2 (p = 0.04) and NOS2 (p < 0.001) were also increased. Therefore, Se concentrations are decreased in the TAA of MFS, which can contribute to a decrease in the activities of TrxR and GPx, and thiol groups. A decrease in the activities of these enzymes can lead to the loss of redox homeostasis, which can, in turn, lead to an increase in the pro-inflammatory interleukins associated with the overexpression of MMP9 and MMP2. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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20 pages, 7532 KiB

Open AccessArticle

PPAR Alpha Activation by Clofibrate Alleviates Ischemia/Reperfusion Injury in Metabolic Syndrome Rats by Decreasing Cardiac Inflammation and Remodeling and by Regulating the Atrial Natriuretic Peptide Compensatory Response

by María Sánchez-Aguilar, Luz Ibarra-Lara, Agustina Cano-Martínez, Elizabeth Soria-Castro, Vicente Castrejón-Téllez, Natalia Pavón, Citlalli Osorio-Yáñez, Eulises Díaz-Díaz and María Esther Rubio-Ruíz

Int. J. Mol. Sci. 2023, 24(6), 5321; https://doi.org/10.3390/ijms24065321 - 10 Mar 2023

Cited by 7 | Viewed by 2208

Abstract

Metabolic syndrome (MetS) is a cluster of factors that increase the risk of developing diabetes, stroke, and heart failure. The pathophysiology of injury by ischemia/reperfusion (I/R) is highly complex and the inflammatory condition plays an important role by increasing matrix remodeling and cardiac [...] Read more.

Metabolic syndrome (MetS) is a cluster of factors that increase the risk of developing diabetes, stroke, and heart failure. The pathophysiology of injury by ischemia/reperfusion (I/R) is highly complex and the inflammatory condition plays an important role by increasing matrix remodeling and cardiac apoptosis. Natriuretic peptides (NPs) are cardiac hormones with numerous beneficial effects mainly mediated by a cell surface receptor named atrial natriuretic peptide receptor (ANPr). Although NPs are powerful clinical markers of cardiac failure, their role in I/R is still controversial. Peroxisome proliferator-activated receptor α agonists exert cardiovascular therapeutic actions; however, their effect on the NPs’ signaling pathway has not been extensively studied. Our study provides important insight into the regulation of both ANP and ANPr in the hearts of MetS rats and their association with the inflammatory conditions caused by damage from I/R. Moreover, we show that pre-treatment with clofibrate was able to decrease the inflammatory response that, in turn, decreases myocardial fibrosis, the expression of metalloprotease 2 and apoptosis. Treatment with clofibrate is also associated with a decrease in ANP and ANPr expression. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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16 pages, 3900 KiB

Open AccessArticle

Anti-Fibrotic Potential of Angiotensin (1-7) in Hemodynamically Overloaded Rat Heart

by Matus Sykora, Vojtech Kratky, Libor Kopkan, Narcisa Tribulova and Barbara Szeiffova Bacova

Int. J. Mol. Sci. 2023, 24(4), 3490; https://doi.org/10.3390/ijms24043490 - 9 Feb 2023

Cited by 7 | Viewed by 1961

Abstract

The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to [...] Read more.

The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to explore ECM and connexin-43 (Cx43) signaling pathways in hemodynamically overloaded rat heart as well as the possible implication of angiotensin (1-7) (Ang (1-7)) to prevent/attenuate adverse myocardial remodeling. Male 8-week-old, normotensive Hannover Spraque–Dawley rats (HSD), hypertensive (mRen-2)27 transgenic rats (TGR) and Ang (1-7) transgenic rats (TGR(A1-7)3292) underwent aortocaval fistula (ACF) to produce volume overload. Five weeks later, biometric and heart tissue analyses were performed. Cardiac hypertrophy in response to volume overload was significantly less pronounced in TGR(A1-7)3292 compared to HSD rats. Moreover, a marker of fibrosis hydroxyproline was increased in both ventricles of volume-overloaded TGR while it was reduced in the Ang (1-7) right heart ventricle. The protein level and activity of MMP-2 were reduced in both ventricles of volume-overloaded TGR/TGR(A1-7)3292 compared to HSD. SMAD2/3 protein levels were decreased in the right ventricle of TGR(A1-7)3292 compared to HSD/TGR in response to volume overload. In parallel, Cx43 and pCx43 implicated in electrical coupling were increased in TGR(A1-7)3292 versus HSD/TGR. It can be concluded that Ang (1-7) exhibits cardio-protective and anti-fibrotic potential in conditions of cardiac volume overload. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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21 pages, 12887 KiB

Open AccessArticle

Neonatal Plasma Exosomes Contribute to Endothelial Cell-Mediated Angiogenesis and Cardiac Repair after Acute Myocardial Infarction

by Xiuya Li, Yilin Lian, Yukang Wu, Zihui Ye, Jiabao Feng, Yuan Zhao, Xudong Guo and Jiuhong Kang

Int. J. Mol. Sci. 2023, 24(4), 3196; https://doi.org/10.3390/ijms24043196 - 6 Feb 2023

Cited by 6 | Viewed by 2795

Abstract

Acute myocardial infarction (AMI) accompanied by cardiac remodeling still lacks effective treatment to date. Accumulated evidences suggest that exosomes from various sources play a cardioprotective and regenerative role in heart repair, but their effects and mechanisms remain intricate. Here, we found that intramyocardial [...] Read more.

Acute myocardial infarction (AMI) accompanied by cardiac remodeling still lacks effective treatment to date. Accumulated evidences suggest that exosomes from various sources play a cardioprotective and regenerative role in heart repair, but their effects and mechanisms remain intricate. Here, we found that intramyocardial delivery of plasma exosomes from neonatal mice (npEXO) could help to repair the adult heart in structure and function after AMI. In-depth proteome and single-cell transcriptome analyses suggested that npEXO ligands were majorly received by cardiac endothelial cells (ECs), and npEXO-mediated angiogenesis might serve as a pivotal reason to ameliorate the infarcted adult heart. We then innovatively constructed systematical communication networks among exosomal ligands and cardiac ECs and the final 48 ligand–receptor pairs contained 28 npEXO ligands (including the angiogenic factors, Clu and Hspg2), which mainly mediated the pro-angiogenic effect of npEXO by recognizing five cardiac EC receptors (Kdr, Scarb1, Cd36, etc.). Together, the proposed ligand–receptor network in our study might provide inspiration for rebuilding the vascular network and cardiac regeneration post-MI. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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12 pages, 2416 KiB

Open AccessArticle

A Straightforward Cytometry-Based Protocol for the Comprehensive Analysis of the Inflammatory Valve Infiltrate in Aortic Stenosis

by Pablo Álvarez-Heredia, José Joaquín Domínguez-del-Castillo, Irene Reina-Alfonso, Carmen Gutiérrez-González, Fakhri Hassouneh, Alexander Batista-Duharte, Antonio Trujillo-Aguilera, Rosalía López-Romero, Ignacio Muñoz, Rafael Solana and Alejandra Pera

Int. J. Mol. Sci. 2023, 24(3), 2194; https://doi.org/10.3390/ijms24032194 - 22 Jan 2023

Cited by 1 | Viewed by 2038

Abstract

Aortic stenosis (AS) is a frequent cardiac disease in old individuals, characterized by valvular calcification, fibrosis, and inflammation. Recent studies suggest that AS is an active inflammatory atherosclerotic-like process. Particularly, it has been suggested that several immune cell types, present in the valve [...] Read more.

Aortic stenosis (AS) is a frequent cardiac disease in old individuals, characterized by valvular calcification, fibrosis, and inflammation. Recent studies suggest that AS is an active inflammatory atherosclerotic-like process. Particularly, it has been suggested that several immune cell types, present in the valve infiltrate, contribute to its degeneration and to the progression toward stenosis. Furthermore, the infiltrating T cell subpopulations mainly consist of oligoclonal expansions, probably specific for persistent antigens. Thus, the characterization of the cells implicated in the aortic valve calcification and the analysis of the antigens to which those cells respond to is of utmost importance to develop new therapies alternative to the replacement of the valve itself. However, calcified aortic valves have been only studied so far by histological and immunohistochemical methods, unable to render an in-depth phenotypical and functional cell profiling. Here we present, for the first time, a simple and efficient cytometry-based protocol that allows the identification and quantification of infiltrating inflammatory leukocytes in aortic valve explants. Our cytometry protocol saves time and facilitates the simultaneous analysis of numerous surface and intracellular cell markers and may well be also applied to the study of other cardiac diseases with an inflammatory component. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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21 pages, 2827 KiB

Open AccessArticle

Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure

by Mingyao Gu, Yuying Zhao, Hong Wang, Wanwen Cheng, Jie Liu, Kunfu Ouyang and Chaoliang Wei

Int. J. Mol. Sci. 2023, 24(2), 1283; https://doi.org/10.3390/ijms24021283 - 9 Jan 2023

Cited by 5 | Viewed by 2327

Abstract

Heart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation [...] Read more.

Heart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation of cardiac function and plays a critical role in the process of heart failure. However, how RBFox2 itself is regulated remains unclear. Here, we dissected transcriptomic signatures, including mRNAs and miRNAs, in a mouse model of heart failure after TAC surgery. A global analysis showed that an asymmetric alternation in gene expression and a large-scale upregulation of miRNAs occurred in heart failure. An association analysis revealed that the latter not only contributed to the degradation of numerous mRNA transcripts, but also suppressed the translation of key proteins such as RBFox2. With the aid of Ago2 CLIP-seq data, luciferase assays verified that RBFox2 was targeted by multiple miRNAs, including Let-7, miR-16, and miR-200b, which were significantly upregulated in heart failure. The overexpression of these miRNAs suppressed the RBFox2 protein and its downstream effects in cardiomyocytes, which was evidenced by the suppressed alternative splicing of the Enah gene and impaired E–C coupling via the repression of the Jph2 protein. The inhibition of Let-7, the most abundant miRNA family targeting RBFox2, could restore the RBFox2 protein as well as its downstream effects in dysfunctional cardiomyocytes induced by ISO treatment. In all, these findings revealed the molecular mechanism leading to RBFox2 depression in heart failure, and provided an approach to rescue RBFox2 through miRNA inhibition for the treatment of heart failure. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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14 pages, 3090 KiB

Open AccessArticle

Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes

by Agnieszka Olejnik, Anna Krzywonos-Zawadzka, Marta Banaszkiewicz and Iwona Bil-Lula

Int. J. Mol. Sci. 2022, 23(24), 15450; https://doi.org/10.3390/ijms232415450 - 7 Dec 2022

Cited by 2 | Viewed by 2071

Abstract

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has [...] Read more.

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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25 pages, 3765 KiB

Open AccessArticle

Serum SELENBP1 and VCL Are Effective Biomarkers for Clinical and Forensic Diagnosis of Coronary Artery Spasm

by Xinyi Lin, Zijie Lin, Xin Zhao, Zheng Liu, Chenchao Xu, Bokang Yu, Pan Gao, Zhimin Wang, Junbo Ge, Yiwen Shen and Liliang Li

Int. J. Mol. Sci. 2022, 23(21), 13266; https://doi.org/10.3390/ijms232113266 - 31 Oct 2022

Cited by 5 | Viewed by 1904

Abstract

Coronary artery spasm (CAS) plays an important role in the pathogenesis of many ischemic heart entities; however, there are no established diagnostic biomarkers for CAS in clinical and forensic settings. This present study aimed to identify such serum biomarkers by establishing a rabbit [...] Read more.

Coronary artery spasm (CAS) plays an important role in the pathogenesis of many ischemic heart entities; however, there are no established diagnostic biomarkers for CAS in clinical and forensic settings. This present study aimed to identify such serum biomarkers by establishing a rabbit CAS provocation model and integrating quantitative serum proteomics, parallel reaction monitoring/mass spectrometry-based targeted proteomics, and partial least-squares discriminant analysis (PLS-DA). Our results suggested that SELENBP1 and VCL were potential candidate biomarkers for CAS. In independent clinical samples, SELENBP1 and VCL were validated to be significantly lower in serum but not blood cells from CAS patients, with the reasons for this possibly due to the decreased secretion from cardiomyocytes. The areas under the curve of the receiver operating characteristics (ROC) analysis were 0.9384 for SELENBP1 and 0.9180 for VCL when diagnosing CAS. The CAS risk decreased by 32.3% and 53.6% for every 10 unit increases in the serum SELENBP1 and VCL, respectively. In forensic samples, serum SELENBP1 alone diagnosed CAS-induced deaths at a sensitivity of 100.0% and specificity of 72.73%, and its combination with VCL yielded a diagnostic specificity of 100.0%, which was superior to the traditional biomarkers of cTnI and CK-MB. Therefore, serum SELENBP1 and VCL could be effective biomarkers for both the clinical and forensic diagnosis of CAS. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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24 pages, 3498 KiB

Open AccessArticle

Genetic Disruption of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Triggers Differential Cardiac Fibrosis and Disorders in Male and Female Mutant Mice: Role of TGF-β1/SMAD Signaling Pathway

by Umadevi Subramanian, Chandramohan Ramasamy, Samivel Ramachandran, Joshua M. Oakes, Jason D. Gardner and Kailash N. Pandey

Int. J. Mol. Sci. 2022, 23(19), 11487; https://doi.org/10.3390/ijms231911487 - 29 Sep 2022

Cited by 2 | Viewed by 1960

Abstract

The global targeted disruption of the natriuretic peptide receptor-A (NPRA) gene (Npr1) in mice provokes hypertension and cardiovascular dysfunction. The objective of this study was to determine the mechanisms regulating the development of cardiac fibrosis and dysfunction in Npr1 mutant mice. [...] Read more.

The global targeted disruption of the natriuretic peptide receptor-A (NPRA) gene (Npr1) in mice provokes hypertension and cardiovascular dysfunction. The objective of this study was to determine the mechanisms regulating the development of cardiac fibrosis and dysfunction in Npr1 mutant mice. Npr1 knockout (Npr1^−/−, 0-copy), heterozygous (Npr1^+/−, 1-copy), and wild-type (Npr1^+/+, 2-copy) mice were treated with the transforming growth factor (TGF)-β1 receptor (TGF-β1R) antagonist GW788388 (2 µg/g body weight/day; ip) for 28 days. Hearts were isolated and used for real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analyses. The Npr1^−/− (0-copy) mice showed a 6-fold induction of cardiac fibrosis and dysfunction with markedly induced expressions of collagen-1α (3.8-fold), monocyte chemoattractant protein (3.7-fold), connective tissue growth factor (CTGF, 5.3-fold), α-smooth muscle actin (α-SMA, 6.1-fold), TGF-βRI (4.3-fold), TGF-βRII (4.7-fold), and phosphorylated small mothers against decapentaplegic (pSMAD) proteins, including pSMAD-2 (3.2-fold) and pSMAD-3 (3.7-fold), compared with wild-type mice. The expressions of phosphorylated extracellular-regulated kinase ERK1/2 (pERK1/2), matrix metalloproteinases-2, -9, (MMP-2, -9), and proliferating cell nuclear antigen (PCNA) were also significantly upregulated in Npr1 0-copy mice. The treatment of mutant mice with GW788388 significantly blocked the expression of fibrotic markers, SMAD proteins, MMPs, and PCNA compared with the vehicle-treated control mice. The treatment with GW788388 significantly prevented cardiac dysfunctions in a sex-dependent manner in Npr1 0-copy and 1-copy mutant mice. The results suggest that the development of cardiac fibrosis and dysfunction in mutant mice is predominantly regulated through the TGF-β1-mediated SMAD-dependent pathway. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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28 pages, 2932 KiB

Open AccessArticle

Altered Expression of TMEM43 Causes Abnormal Cardiac Structure and Function in Zebrafish

by Miriam Zink, Anne Seewald, Mareike Rohrbach, Andreas Brodehl, Daniel Liedtke, Tatjana Williams, Sarah J. Childs and Brenda Gerull

Int. J. Mol. Sci. 2022, 23(17), 9530; https://doi.org/10.3390/ijms23179530 - 23 Aug 2022

Cited by 6 | Viewed by 3855

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular arrhythmias and sudden cardiac death. However, the role of TMEM43 in the pathogenesis of ACM remains poorly understood. In this study, we generated cardiomyocyte-restricted transgenic zebrafish lines that overexpress eGFP-linked full-length human wild-type (WT) TMEM43 and two genetic variants (c.1073C>T, p.S358L; c.332C>T, p.P111L) using the Tol2-system. Overexpression of WT and p.P111L-mutant TMEM43 was associated with transcriptional activation of the mTOR pathway and ribosome biogenesis, and resulted in enlarged hearts with cardiomyocyte hypertrophy. Intriguingly, mutant p.S358L TMEM43 was found to be unstable and partially redistributed into the cytoplasm in embryonic and adult hearts. Moreover, both TMEM43 variants displayed cardiac morphological defects at juvenile stages and ultrastructural changes within the myocardium, accompanied by dysregulated gene expression profiles in adulthood. Finally, CRISPR/Cas9 mutants demonstrated an age-dependent cardiac phenotype characterized by heart enlargement in adulthood. In conclusion, our findings suggest ultrastructural remodeling and transcriptomic alterations underlying the development of structural and functional cardiac defects in TMEM43-associated cardiomyopathy. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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Review

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18 pages, 1597 KiB

Open AccessReview

An Overview of the Cardioprotective Effects of Novel Antidiabetic Classes: Focus on Inflammation, Oxidative Stress, and Fibrosis

by Dora Bianka Balogh, Laszlo Jozsef Wagner and Andrea Fekete

Int. J. Mol. Sci. 2023, 24(9), 7789; https://doi.org/10.3390/ijms24097789 - 24 Apr 2023

Cited by 11 | Viewed by 3288

Abstract

Metabolic diseases, particularly diabetes mellitus (DM), are significant global public health concerns. Despite the widespread use of standard-of-care therapies, cardiovascular disease (CVD) remains the leading cause of death among diabetic patients. Early and evidence-based interventions to reduce CVD are urgently needed. Large clinical [...] Read more.

Metabolic diseases, particularly diabetes mellitus (DM), are significant global public health concerns. Despite the widespread use of standard-of-care therapies, cardiovascular disease (CVD) remains the leading cause of death among diabetic patients. Early and evidence-based interventions to reduce CVD are urgently needed. Large clinical trials have recently shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) ameliorate adverse cardiorenal outcomes in patients with type 2 DM. These quite unexpected positive results represent a paradigm shift in type 2 DM management, from the sole importance of glycemic control to the simultaneous improvement of cardiovascular outcomes. Moreover, SGLT2i is also found to be cardio- and nephroprotective in non-diabetic patients. Several mechanisms, which may be potentially independent or at least separate from the reduction in blood glucose levels, have already been identified behind the beneficial effect of these drugs. However, there is still much to be understood regarding the exact pathomechanisms. This review provides an overview of the current literature and sheds light on the modes of action of novel antidiabetic drugs, focusing on inflammation, oxidative stress, and fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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18 pages, 906 KiB

Open AccessReview

Extracellular Vesicles in Adipose Tissue Communication with the Healthy and Pathological Heart

by Lauriane Y. M. Michel

Int. J. Mol. Sci. 2023, 24(9), 7745; https://doi.org/10.3390/ijms24097745 - 24 Apr 2023

Cited by 10 | Viewed by 2630

Abstract

Adipose tissue and its diverse cell types constitute one of the largest endocrine organs. With multiple depot locations, adipose tissue plays an important regulatory role through paracrine and endocrine communication, particularly through the secretion of a wide range of bioactive molecules, such as [...] Read more.

Adipose tissue and its diverse cell types constitute one of the largest endocrine organs. With multiple depot locations, adipose tissue plays an important regulatory role through paracrine and endocrine communication, particularly through the secretion of a wide range of bioactive molecules, such as nucleic acids, proteins, lipids or adipocytokines. Over the past several years, research has uncovered a myriad of interorgan communication signals mediated by small lipid-derived nanovesicles known as extracellular vesicles (EVs), in which secreted bioactive molecules are stably transported as cargo molecules and delivered to adjacent cells or remote organs. EVs constitute an essential part of the human adipose secretome, and there is a growing body of evidence showing the crucial implications of adipose-derived EVs in the regulation of heart function and its adaptative capacity. The adipose tissue modifications and dysfunction observed in obesity and aging tremendously affect the adipose-EV secretome, with important consequences for the myocardium. The present review presents a comprehensive analysis of the findings in this novel area of research, reports the key roles played by adipose-derived EVs in interorgan cross-talk with the heart and discusses their implications in physiological and pathological conditions affecting adipose tissue and/or the heart (pressure overload, ischemia, diabetic cardiomyopathy, etc.). Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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15 pages, 9274 KiB

Open AccessReview

Small Extracellular Vesicles Derived from Induced Pluripotent Stem Cells in the Treatment of Myocardial Injury

by Wan-Ting Meng and Hai-Dong Guo

Int. J. Mol. Sci. 2023, 24(5), 4577; https://doi.org/10.3390/ijms24054577 - 26 Feb 2023

Cited by 7 | Viewed by 3778

Abstract

Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction [...] Read more.

Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction between iPSCs and target cells. In recent years, more and more studies have focused on the therapeutic effect of iPSCs-sEVs in myocardial injury. IPSCs-sEVs may be a new cell-free-based treatment for myocardial injury, including myocardial infarction, myocardial ischemia–reperfusion injury, coronary heart disease, and heart failure. In the current research on myocardial injury, the extraction of sEVs from mesenchymal stem cells induced by iPSCs was widely used. Isolation methods of iPSCs-sEVs for the treatment of myocardial injury include ultracentrifugation, isodensity gradient centrifugation, and size exclusion chromatography. Tail vein injection and intraductal administration are the most widely used routes of iPSCs-sEV administration. The characteristics of sEVs derived from iPSCs which were induced from different species and organs, including fibroblasts and bone marrow, were further compared. In addition, the beneficial genes of iPSC can be regulated through CRISPR/Cas9 to change the composition of sEVs and improve the abundance and expression diversity of them. This review focused on the strategies and mechanisms of iPSCs-sEVs in the treatment of myocardial injury, which provides a reference for future research and the application of iPSCs-sEVs. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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23 pages, 730 KiB

Open AccessReview

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

by Matteo Ponzoni, John G. Coles and Jason T. Maynes

Int. J. Mol. Sci. 2023, 24(4), 3162; https://doi.org/10.3390/ijms24043162 - 5 Feb 2023

Cited by 8 | Viewed by 4000

Abstract

Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first [...] Read more.

Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first key step for reliable and translatable experimental research. Rodent models of heart failure provide a strategic compromise between human in vivo similarity and the ability to perform a larger number of experiments and explore many therapeutic candidates. We herein review the currently available rodent models of heart failure, summarizing their physiopathological basis, the timeline of the development of ventricular failure, and their specific clinical features. In order to facilitate the future planning of investigations in the field of heart failure, a detailed overview of the advantages and possible drawbacks of each model is provided. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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21 pages, 1895 KiB

Open AccessReview

Cellular Mechanisms Underlying the Cardioprotective Role of Allicin on Cardiovascular Diseases

by José L. Sánchez-Gloria, Abraham S. Arellano-Buendía, Juan G. Juárez-Rojas, Fernando E. García-Arroyo, Raúl Argüello-García, Fausto Sánchez-Muñoz, Laura G. Sánchez-Lozada and Horacio Osorio-Alonso

Int. J. Mol. Sci. 2022, 23(16), 9082; https://doi.org/10.3390/ijms23169082 - 13 Aug 2022

Cited by 21 | Viewed by 4618

Abstract

Cardiovascular diseases (CVDs) are a group of diseases in which the common denominator is the affection of blood vessels, heart tissue, and heart rhythm. The genesis of CVD is complex and multifactorial; therefore, approaches are often based on multidisciplinary management and more than [...] Read more.

Cardiovascular diseases (CVDs) are a group of diseases in which the common denominator is the affection of blood vessels, heart tissue, and heart rhythm. The genesis of CVD is complex and multifactorial; therefore, approaches are often based on multidisciplinary management and more than one drug is used to achieve the optimal control of risk factors (dyslipidemia, hypertension, hypertrophy, oxidative stress, endothelial dysfunction, inflammation). In this context, allicin, a sulfur compound naturally derived from garlic, has shown beneficial effects on several cardiovascular risk factors through the modulation of cellular mechanisms and signaling pathways. Effective pharmacological treatments for CVD or its risk factors have not been developed or are unknown in clinical practice. Thus, this work aimed to review the cellular mechanisms through which allicin exerts its therapeutic effects and to show why it could be a therapeutic option for the prevention or treatment of CVD and its risk factors. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Heart Diseases)

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