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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 18643

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Prof. Dr. Mirela Cleopatra Tomescu

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Department of Internal Medicine, Victor Babes University of Medicine and Pharmacy of Timisoara, Timisoara, Romania
Interests: cardiology; coronary artery disease; heart failure; arrhythmias; imaging; echocardiography
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular cardiology is a new and fast-growing area of cardiovascular medicine that aims to apply molecular biology techniques for the mechanistic investigation, diagnosis, prevention and treatment of cardiovascular disease.

As an emerging discipline, it has changed our conceptual thinking of cardiovascular development, disease etiology and pathophysiology. Although molecular cardiology is still at a very early stage, it has opened a promising avenue for understanding and controlling cardiovascular disease.

The Special Issue will address the recent advances in the molecular pathophysiology of cardiovascular disease, including gene analysis in injured and hypertrophied hearts; transgenic techniques in cardiac research; gene transfer and gene therapy for cardiovascular disease; and stem cell therapy for cardiovascular disease.

It would be an honor to publish your article in the upcoming Special Issue of our journal. Therefore, we kindly request you to submit a manuscript. This Special Issue is supervised by Dr. Mirela Cleopatra Tomescu and assisted by our Topical Advisory Panel Member, Dr. Sourav Ghorai (University of Illinois at Chicago).

Prof. Dr. Mirela Cleopatra Tomescu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

DNA
genes
heart diseases
hypertrophy
molecular biology
myocardial infarction

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Published Papers (9 papers)

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Research

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15 pages, 3691 KiB

Open AccessArticle

CD38 Deficiency Alleviates Diabetic Cardiomyopathy by Coordinately Inhibiting Pyroptosis and Apoptosis

by Ling-Fang Wang, Qian Li, Ke Wen, Qi-Hang Zhao, Ya-Ting Zhang, Jia-Le Zhao, Qi Ding, Xiao-Hui Guan, Yun-Fei Xiao, Ke-Yu Deng and Hong-Bo Xin

Int. J. Mol. Sci. 2023, 24(21), 16008; https://doi.org/10.3390/ijms242116008 - 6 Nov 2023

Cited by 8 | Viewed by 2392

Abstract

Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD⁺ in mammals, plays an important role in various cardiovascular diseases, according to our previous studies. However, the role of CD38 in diabetes-induced cardiomyopathy is still unknown. Here, we report that global deletion of the CD38 gene significantly prevented diabetic cardiomyopathy induced by high-fat diet plus streptozotocin (STZ) injection in CD38 knockout (CD38-KO) mice. We observed that CD38 expression was up-regulated, whereas the expression of Sirt3 was down-regulated in the hearts of diabetic mice. CD38 deficiency significantly promoted glucose metabolism and improved cardiac functions, exemplified by increased left ventricular ejection fraction and fractional shortening. In addition, we observed that CD38 deficiency markedly decreased diabetes or high glucose and palmitic acid (HG + PA)-induced pyroptosis and apoptosis in CD38 knockout hearts or cardiomyocytes, respectively. Furthermore, we found that the expression levels of Sirt3, mainly located in mitochondria, and its target gene FOXO3a were increased in CD38-deficient hearts and cardiomyocytes with CD38 knockdown under diabetic induction conditions. In conclusion, we demonstrated that CD38 deficiency protected mice from diabetes-induced diabetic cardiomyopathy by reducing pyroptosis and apoptosis via activating NAD⁺/Sirt3/FOXO3a signaling pathways. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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27 pages, 962 KiB

Open AccessArticle

Single-Nucleotide Polymorphism in Genes Encoding G Protein Subunits GNB3 and GNAQ Increase the Risk of Cardiovascular Morbidity among Patients Undergoing Renal Replacement Therapy

by Simon Birkner, Birte Möhlendick, Benjamin Wilde, Kristina Schoenfelder, Kristina Boss, Winfried Siffert, Andreas Kribben and Justa Friebus-Kardash

Int. J. Mol. Sci. 2023, 24(20), 15260; https://doi.org/10.3390/ijms242015260 - 17 Oct 2023

Viewed by 1177

Abstract

Single-nucleotide polymorphisms in G protein subunits are linked to an increased risk of cardiovascular events among the general population. We assessed the effects of GNB3 c.825C > T, GNAQ −695/−694GC > TT, and GNAS c.393C > T polymorphisms on the risk of cardiovascular events among 454 patients undergoing renal replacement therapy. The patients were followed up for a median of 4.5 years after the initiation of dialysis. Carriers of the TT/TT genotype of GNAQ required stenting because of coronary artery stenosis (p = 0.0009) and developed cardiovascular events involving more than one organ system (p = 0.03) significantly earlier and more frequently than did the GC/TT or GC/GC genotypes. Multivariate analysis found that the TT/TT genotype of GNAQ was an independent risk factor for coronary artery stenosis requiring stent (hazard ratio, 4.5; p = 0.001), cardiovascular events (hazard ratio, 1.93; p = 0.04) and cardiovascular events affecting multiple organs (hazard ratio, 4.9; p = 0.03). In the subgroup of male patients left ventricular dilatation with abnormally increased LVEDD values occurred significantly more frequently in TT genotypes of GNB3 than in CT/CC genotypes (p = 0.007). Our findings suggest that male dialysis patients carrying the TT genotype of GNB3 are at higher risk of left ventricular dilatation and that dialysis patients carrying the TT/TT genotype of GNAQ are prone to coronary artery stenosis and severe cardiovascular events. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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22 pages, 7316 KiB

Open AccessArticle

Embedding and Backscattered Scanning Electron Microscopy (EM-BSEM) Is Preferential over Immunophenotyping in Relation to Bioprosthetic Heart Valves

by Alexander Kostyunin, Tatiana Glushkova, Elena Velikanova, Rinat Mukhamadiyarov, Leo Bogdanov, Tatiana Akentyeva, Evgeny Ovcharenko, Alexey Evtushenko, Daria Shishkova, Yulia Markova and Anton Kutikhin

Int. J. Mol. Sci. 2023, 24(17), 13602; https://doi.org/10.3390/ijms241713602 - 2 Sep 2023

Cited by 1 | Viewed by 1242

Abstract

Hitherto, calcified aortic valves (AVs) and failing bioprosthetic heart valves (BHVs) have been investigated by similar approaches, mostly limited to various immunostaining techniques. Having employed multiple immunostaining combinations, we demonstrated that AVs retain a well-defined cellular hierarchy even at severe stenosis, whilst BHVs were notable for the stochastic degradation of the extracellular matrix (ECM) and aggressive infiltration by ECM-digesting macrophages. Leukocytes (CD45⁺) comprised ≤10% cells in the AVs but were the predominant cell lineage in BHVs (≥80% cells). Albeit cells with uncertain immunophenotype were rarely encountered in the AVs (≤5% cells), they were commonly found in BHVs (≥80% cells). Whilst cell conversions in the AVs were limited to the endothelial-to-mesenchymal transition (represented by CD31⁺α-SMA⁺ cells) and the formation of endothelial-like (CD31⁺CD68⁺) cells at the AV surface, BHVs harboured numerous macrophages with a transitional phenotype, mostly CD45⁺CD31⁺, CD45⁺α-SMA⁺, and CD68⁺α-SMA⁺. In contrast to immunostaining, which was unable to predict cell function in the BHVs, our whole-specimen, nondestructive electron microscopy approach (EM-BSEM) was able to distinguish between quiescent and matrix-degrading macrophages, foam cells, and multinucleated giant cells to conduct the ultrastructural analysis of organelles and the ECM, and to preserve tissue integrity. Hence, we suggest EM-BSEM as a technique of choice for studying the cellular landscape of BHVs. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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42 pages, 15076 KiB

Open AccessArticle

SARS-CoV-2 and Its Bacterial Co- or Super-Infections Synergize to Trigger COVID-19 Autoimmune Cardiopathies

by Robert Root-Bernstein, Jack Huber, Alison Ziehl and Maja Pietrowicz

Int. J. Mol. Sci. 2023, 24(15), 12177; https://doi.org/10.3390/ijms241512177 - 29 Jul 2023

Cited by 3 | Viewed by 1769

Abstract

Autoimmune cardiopathies (AC) following COVID-19 and vaccination against SARS-CoV-2 occur at significant rates but are of unknown etiology. This study investigated the possible roles of viral and bacterial mimicry, as well as viral-bacterial co-infections, as possible inducers of COVID-19 AC using proteomic methods and enzyme-linked immunoadsorption assays. BLAST and LALIGN results of this study demonstrate that SARS-CoV-2 shares a significantly greater number of high quality similarities to some cardiac protein compared with other viruses; that bacteria such as Streptococci, Staphylococci and Enterococci also display very significant similarities to cardiac proteins but to a different set than SARS-CoV-2; that the importance of these similarities is largely validated by ELISA experiments demonstrating that polyclonal antibodies against SARS-CoV-2 and COVID-19-associated bacteria recognize cardiac proteins with high affinity; that to account for the range of cardiac proteins targeted by autoantibodies in COVID-19-associated autoimmune myocarditis, both viral and bacterial triggers are probably required; that the targets of the viral and bacterial antibodies are often molecularly complementary antigens such as actin and myosin, laminin and collagen, or creatine kinase and pyruvate kinase, that are known to bind to each other; and that the corresponding viral and bacterial antibodies recognizing these complementary antigens also bind to each other with high affinity as if they have an idiotype-anti-idiotype relationship. These results suggest that AC results from SARS-CoV-2 infections or vaccination complicated by bacterial infections. Vaccination against some of these bacterial infections, such as Streptococci and Haemophilus, may therefore decrease AC risk, as may the appropriate and timely use of antibiotics among COVID-19 patients and careful screening of vaccinees for signs of infection such as fever, diarrhea, infected wounds, gum disease, etc. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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18 pages, 12622 KiB

Open AccessArticle

LncRNA GAS5 Attenuates Cardiac Electrical Remodeling Induced by Rapid Pacing via the miR-27a-3p/HOXa10 Pathway

by Siqi Xi, Hao Wang, Jindong Chen, Tian Gan and Liang Zhao

Int. J. Mol. Sci. 2023, 24(15), 12093; https://doi.org/10.3390/ijms241512093 - 28 Jul 2023

Cited by 1 | Viewed by 1321

Abstract

Previous studies indicated long non-coding RNAs (lncRNAs) participated in the pathogenesis of atrial fibrillation (AF). However, little is known about the role of lncRNAs in AF-induced electrical remodeling. This study aimed to investigate the regulatory effect of lncRNA GAS5 (GAS5) on the electrical remodeling of neonatal rat cardiomyocytes (NRCMs) induced by rapid pacing (RP). RNA microarray analysis yielded reduced GAS5 level in NRCMs after RP. RT-qPCR, western blot, and immunofluorescence yielded downregulated levels of Nav1.5, Kv4.2, and Cav1.2 after RP, and whole-cell patch-clamp yielded decreased sodium, potassium, and calcium current. Overexpression of GAS5 attenuated electrical remodeling. Bioinformatics tool prediction analysis and dual luciferase reporter assay confirmed a direct negative regulatory effect for miR-27a-3p on lncRNA-GAS5 and HOXa10. Further analysis demonstrated that either miR-27a-3p overexpression or the knockdown of HOXa10 further downregulated Nav1.5, Kv4.2, and Cav1.2 expression. GAS5 overexpression antagonized such effects in Nav1.5 and Kv4.2 but not in Cav1.2. These results indicate that, in RP-treated NRCMs, GAS5 could restore Nav1.5 and Kv4.2 expression via the miR-27a-3p/HOXa10 pathway. However, the mechanism of GAS5 restoring Cav1.2 level remains unclear. Our study suggested that GAS5 regulated cardiac ion channels via the GAS5/miR-27a-3p/HOXa10 pathway and might be a potential therapeutic target for AF. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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11 pages, 903 KiB

Open AccessArticle

Clinical and Biological Predictors of Cancer Incidence and Mortality in Patients with Stable Coronary Artery Disease

by Jonica Campolo, Andrea Borghini, Marina Parolini, Antonella Mercuri, Stefano Turchi and Maria Grazia Andreassi

Int. J. Mol. Sci. 2023, 24(13), 11091; https://doi.org/10.3390/ijms241311091 - 4 Jul 2023

Cited by 2 | Viewed by 1766

Abstract

Clinical and epidemiological evidence has recently revealed a link between coronary artery disease (CAD) and cancer. Shared risk factors and common biological pathways are probably involved in both pathological conditions. The aim of this paper was to evaluate whether and which conventional risk factors and novel circulating biomarkers could predict cancer incidence and death in patients with CAD. The study included 750 CAD patients, who underwent blood sampling for the evaluation of systemic inflammatory indexes (NLR and SII) and specific biomarkers of oxidative damage (leukocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)). Study participants were followed up for a mean of 5.4 ± 1.2 years. Sixty-seven patients (8.9%) developed cancer during the follow-up time, and nineteen (2.5%) died of cancer. Cox multivariable analysis revealed that age (HR = 1.071; 95% CI: 1.034–1.109; p < 0.001), smoking habit (HR = 1.994; 95% CI: 1.140–3.488; p = 0.016), obesity (HR = 1.708; 95% CI: 1.022–2.854; p = 0.041) and SII (HR = 1.002; 95% CI: 1.001–1.003; p = 0.045) were associated with cancer incidence, while only age (HR = 1.132; 95% CI: 1.052–1.219; p = 0.001) was a predictor of cancer death. Patients with lung and gastrointestinal cancers had significantly higher median mtDNAcn levels than those without cancer. Our study suggests that aggressive risk factor modification and suppression of chronic inflammation may be essential to preventing cancer in CAD patients. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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17 pages, 3335 KiB

Open AccessArticle

Expression of Ceramide-Metabolizing Enzymes in the Heart Adipose Tissue of Cardiovascular Disease Patients

by Olga Gruzdeva, Yulia Dyleva, Ekaterina Belik, Evgenia Uchasova, Anastasia Ponasenko, Sergey Ivanov, Maxim Zinets, Alexander Stasev, Anton Kutikhin, Victoria Markova, Alena Poddubnyak, Evgenia Gorbatovskaya, Elena Fanaskova and Olga Barbarash

Int. J. Mol. Sci. 2023, 24(11), 9494; https://doi.org/10.3390/ijms24119494 - 30 May 2023

Cited by 2 | Viewed by 2170

Abstract

Here, we examined the expression of ceramide metabolism enzymes in the subcutaneous adipose tissue (SAT), epicardial adipose tissue (EAT) and perivascular adipose tissue (PVAT) of 30 patients with coronary artery disease (CAD) and 30 patients with valvular heart disease (VHD) by means of quantitative polymerase chain reaction and fluorescent Western blotting. The EAT of patients with CAD showed higher expression of the genes responsible for ceramide biosynthesis (SPTLC1, SPTLC2, CERS1, 5, 6, DEGS1, and SMPD1) and utilization (ASAH1, SGMS1). PVAT was characterized by higher mRNA levels of CERS3, CERS4, DEGS1, SMPD1, and ceramide utilization enzyme (SGMS2). In patients with VHD, there was a high CERS4, DEGS1, and SGMS2 expression in the EAT and CERS3 and CERS4 expression in the PVAT. Among patients with CAD, the expression of SPTLC1 in SAT and EAT, SPTLC2 in EAT, CERS2 in all studied AT, CERS4 and CERS5 in EAT, DEGS1 in SAT and EAT, ASAH1 in all studied AT, and SGMS1 in EAT was higher than in those with VHD. Protein levels of ceramide-metabolizing enzymes were consistent with gene expression trends. The obtained results indicate an activation of ceramide synthesis de novo and from sphingomyelin in cardiovascular disease, mainly in EAT, that contributes to the accumulation of ceramides in this location. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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Review

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24 pages, 2191 KiB

Open AccessReview

Long Non-Coding RNAs in Venous Thromboembolism: Where Do We Stand?

by Inês Soares Marques, Valéria Tavares, Beatriz Vieira Neto, Inês N. R. Mota, Deolinda Pereira and Rui Medeiros

Int. J. Mol. Sci. 2023, 24(15), 12103; https://doi.org/10.3390/ijms241512103 - 28 Jul 2023

Cited by 5 | Viewed by 2486

Abstract

Venous thromboembolism (VTE), a common condition in Western countries, is a cardiovascular disorder that arises due to haemostatic irregularities, which lead to thrombus generation inside veins. Even with successful treatment, the resulting disease spectrum of complications considerably affects the patient’s quality of life, potentially leading to death. Cumulative data indicate that long non-coding RNAs (lncRNAs) may have a role in VTE pathogenesis. However, the clinical usefulness of these RNAs as biomarkers and potential therapeutic targets for VTE management is yet unclear. Thus, this article reviewed the emerging evidence on lncRNAs associated with VTE and with the activity of the coagulation system, which has a central role in disease pathogenesis. Until now, ten lncRNAs have been implicated in VTE pathogenesis, among which MALAT1 is the one with more evidence. Meanwhile, five lncRNAs have been reported to affect the expression of TFPI2, an important anticoagulant protein, but none with a described role in VTE development. More investigation in this field is needed as lncRNAs may help dissect VTE pathways, aiding in disease prediction, prevention and treatment. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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34 pages, 3258 KiB

Open AccessReview

Host–Bacterium Interaction Mechanisms in Staphylococcus aureus Endocarditis: A Systematic Review

by Francesco Nappi and Sanjeet Singh Avtaar Singh

Int. J. Mol. Sci. 2023, 24(13), 11068; https://doi.org/10.3390/ijms241311068 - 4 Jul 2023

Cited by 6 | Viewed by 2822

Abstract

Staphylococci sp. are the most commonly associated pathogens in infective endocarditis, especially within high-income nations. This along with the increasing burden of healthcare, aging populations, and the protracted infection courses, contribute to a significant challenge for healthcare systems. A systematic review was conducted using relevant search criteria from PubMed, Ovid’s version of MEDLINE, and EMBASE, and data were tabulated from randomized controlled trials (RCT), observational cohort studies, meta-analysis, and basic research articles. The review was registered with the OSF register of systematic reviews and followed the PRISMA reporting guidelines. Thirty-five studies met the inclusion criteria and were included in the final systematic review. The role of Staphylococcus aureus and its interaction with the protective shield and host protection functions was identified and highlighted in several studies. The interaction between infective endocarditis pathogens, vascular endothelium, and blood constituents was also explored, giving rise to the potential use of antiplatelets as preventative and/or curative agents. Several factors allow Staphylococcus aureus infections to proliferate within the host with numerous promoting and perpetuating agents. The complex interaction with the hosts’ innate immunity also potentiates its virulence. The goal of this study is to attain a better understanding on the molecular pathways involved in infective endocarditis supported by S. aureus and whether therapeutic avenues for the prevention and treatment of IE can be obtained. The use of antibiotic-treated allogeneic tissues have marked antibacterial action, thereby becoming the ideal substitute in native and prosthetic valvular infections. However, the development of effective vaccines against S. aureus still requires in-depth studies. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathophysiology of Cardiovascular Diseases)

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