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Molecular Research in Cardiovascular Disease 2.0

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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 (30 November 2022) | Viewed by 15998

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Prof. Dr. Maria I. Dorobantu

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1. Corresponding member of the Romanian Academiy, 125, Calea Victoriei, Sector 1, RO - 010071 Bucharest, Romania
2. Department 4-Cardiothoracic Pathology, University of Medicine and Pharmacy Carol Davila, 8, Eroii Sanitari Bvd., 050474 Bucharest, Romania
Interests: ischemic heart disease; atherosclerosis; molecular mechanisms of acute coronary syndromes; arterial hypertension; hypertensive target organ damage
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Prof. Dr. Maya Simionescu

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Guest Editor

Romanian Academy-President of the Section of Biological Sciences, Institute of Cellular Biology and Pathology “N. Simionescu”, Bucharest, Romania
Interests: atherosclerosis, cellular, and molecular mechanisms; endothelium; transport of molecules; microcirculation; patho-biochemistry of diabetes mellitus
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Special Issue Information

Dear Colleagues,

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Atherosclerosis, the dominant driver of CVD, is characterized by a process of chronic inflammation and endothelial dysfunction associated with vessel wall accumulation of oxidized low-density lipoproteins.

In advanced stages, endothelial lesions promote atherosclerotic plaque instability, acute events, and ultimately, plaque rupture.

The molecular and cellular mechanisms underlying various cardiovascular diseases are not completely understood. However, several signaling pathways that induce vascular remodeling are essential in both coronary heart disease and in related pathologies, such as pulmonary artery hypertension, suggesting the existence of common mechanisms in these maladies.

With this Special Issue, we aim to present representative data obtained at the interface between basic science and clinical research on the molecular mechanisms of heart and vascular diseases and the novel biomarkers and molecules that can become specific targets for future therapeutic interventions. In addition, we hope that the papers presented will inspire novel innovative investigations at the bench to bedside intersection.

Prof. Dr. Maria I. Dorobantu
Prof. Dr. Maya Simionescu
Guest Editors

Manuscript Submission Information

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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

atherosclerosis
cardiovascular disease
endothelial cells
matrix metalloproteinases
biomarkers
miRNAs
epigenetics

Related Special Issue

Molecular Research in Cardiovascular Disease in International Journal of Molecular Sciences (11 articles)

Published Papers (7 papers)

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Research

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20 pages, 4252 KiB

Open AccessArticle

G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction

by Tina Haase, Christian Müller, Bastian Stoffers, Philipp Kirn, Melanie Waldenberger, Frank J. Kaiser, Mahir Karakas, Sangwon V. Kim, Svenja Voss, Philipp S. Wild, Karl J. Lackner, Jonas Andersson, Stefan Söderberg, Diana Lindner and Tanja Zeller

Int. J. Mol. Sci. 2023, 24(1), 180; https://doi.org/10.3390/ijms24010180 - 22 Dec 2022

Cited by 5 | Viewed by 1754

Abstract

Beyond the influence of lifestyle-related risk factors for myocardial infarction (MI), the mechanisms of genetic predispositions for MI remain unclear. We sought to identify and characterize differentially expressed genes in early-onset MI in a translational approach. In an observational case–control study, transcriptomes from 112 early-onset MI individuals showed upregulated G protein-coupled receptor 15 (GPR15) expression in peripheral blood mononuclear cells compared to controls (fold change = 1.4, p = 1.87 × 10⁻⁷). GPR15 expression correlated with intima-media thickness (β = 0.8498, p = 0.111), C-reactive protein (β = 0.2238, p = 0.0052), ejection fraction (β = −0.9991, p = 0.0281) and smoking (β = 0.7259, p = 2.79 × 10⁻¹⁰). The relation between smoking and MI was diminished after the inclusion of GPR15 expression as mediator in mediation analysis (from 1.27 (p = 1.9 × 10⁻⁵) to 0.46 (p = 0.21)). The DNA methylation of two GPR15 sites was 1%/5% lower in early-onset MI individuals versus controls (p = 2.37 × 10⁻⁶/p = 0.0123), with site CpG3.98251219 significantly predicting risk for incident MI (hazard ratio = 0.992, p = 0.0177). The nucleotide polymorphism rs2230344 (C/T) within GPR15 was associated with early-onset MI (odds ratio = 3.61, p = 0.044). Experimental validation showed 6.3-fold increased Gpr15 expression in an ischemic mouse model (p < 0.05) and 4-fold increased Gpr15 expression in cardiomyocytes under ischemic stress (p < 0.001). After the induction of MI, Gpr15^gfp/gfp mice showed lower survival (p = 0.042) and deregulated gene expression for response to hypoxia and signaling pathways. Using a translational approach, our data provide evidence that GPR15 is linked to cardiovascular diseases, mediating the adverse effects of smoking. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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11 pages, 1263 KiB

Open AccessCommunication

Acute Exposure to Glycated Proteins Impaired in the Endothelium-Dependent Aortic Relaxation: A Matter of Oxidative Stress

by Sarah D’Haese, Dorien Deluyker and Virginie Bito

Int. J. Mol. Sci. 2022, 23(23), 14916; https://doi.org/10.3390/ijms232314916 - 29 Nov 2022

Cited by 1 | Viewed by 1121

Abstract

Chronically increased levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to induce cardiovascular dysfunction. Whether an acute increase in HMW-AGE levels affects vascular function remains unknown. In this study, we examined whether acute exposure to HMW-AGEs disturbs aortic vasomotor function. Aortae were obtained from healthy male rats and were acutely pre-treated with HMW-AGEs in organ baths. Aortic relaxation responses to cumulative doses of acetylcholine (ACh), in the presence or absence of superoxide dismutase (SOD), were measured after precontraction with phenylephrine (PE). Furthermore, levels of 3-nitrotyrosine were evaluated on aortic paraffine sections. In our study, we show that acute exposure to HMW-AGEs significantly decreases the aortic relaxation response to ACh. SOD pre-treatment prevents acute HMW-AGEs-induced impairment by limiting superoxide formation. In conclusion, our data demonstrate that acute exposure to HMW-AGEs causes adverse vascular remodelling, characterised by disturbed vasomotor function due to increased oxidative stress. These results create opportunities for future research regarding the acute role of HMW-AGEs in cardiovascular dysfunction. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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20 pages, 2884 KiB

Open AccessArticle

Mitochondrial DNA Together with miR-142-3p in Plasma Can Predict Unfavorable Outcomes in Patients after Acute Myocardial Infarction

by Teodora Barbalata, Alina I. Scarlatescu, Gabriela M. Sanda, Laura Toma, Camelia S. Stancu, Maria Dorobantu, Miruna M. Micheu, Anca V. Sima and Loredan S. Niculescu

Int. J. Mol. Sci. 2022, 23(17), 9947; https://doi.org/10.3390/ijms23179947 - 01 Sep 2022

Cited by 4 | Viewed by 1292

Abstract

Myocardial infarction is one of the leading causes of death worldwide, despite numerous efforts to find efficient prognostic biomarkers and treatment targets. In the present study, we aimed to assess the potential of six microRNAs known to be involved in cardiovascular diseases, cell-free DNA (cfDNA), and mitochondrial DNA (mtDNA) circulating in plasma to be used as prognostic tools for the occurrence of unfavorable outcomes such as major adverse cardiovascular events (MACE) after acute ST-segment elevation myocardial infarction (STEMI). Fifty STEMI patients were enrolled and monitored for 6 months for the occurrence of MACE. Plasma was collected at three time points: upon admission to hospital (T₀), at discharge from hospital (T₁), and 6 months post-STEMI (T₆). Plasma levels of miR-223-3p, miR-142-3p, miR-155-5p, miR-486-5p, miR-125a-5p, and miR-146a-5p, as well as of cfDNA and mtDNA, were measured by RT-qPCR. Results showed that the levels of all measured miRNAs, as well as of cfDNA and mtDNA, were the most increased at T₁, compared to the other two time points. In the plasma of STEMI patients with MACE compared to those without MACE, we determined increased levels of miRNAs, cfDNA, and mtDNA at T_1. Hence, we used the levels of all measured parameters at T₁ for further statistical analysis. Statistical analysis demonstrated that all six miRNAs and cfDNA plus mtDNA levels, respectively, were associated with MACE. The minimal statistical model that could predict MACE in STEMI patients was the combination of mtDNA and miR-142-3p levels, as evidenced by ROC analysis (AUC = 0.97, p < 0.001). In conclusion, the increased plasma levels of mtDNA, along with miR-142-3p, could be used to predict unfavorable outcomes in STEMI patients. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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22 pages, 3975 KiB

Open AccessArticle

Short-Term Blockade of Pro-Inflammatory Alarmin S100A9 Favorably Modulates Left Ventricle Proteome and Related Signaling Pathways Involved in Post-Myocardial Infarction Recovery

by Raluca Maria Boteanu, Viorel-Iulian Suica, Elena Uyy, Luminita Ivan, Aurel Cerveanu-Hogas, Razvan Gheorghita Mares, Maya Simionescu, Alexandru Schiopu and Felicia Antohe

Int. J. Mol. Sci. 2022, 23(9), 5289; https://doi.org/10.3390/ijms23095289 - 09 May 2022

Cited by 5 | Viewed by 2465

Abstract

Prognosis after myocardial infarction (MI) varies greatly depending on the extent of damaged area and the management of biological processes during recovery. Reportedly, the inhibition of the pro-inflammatory S100A9 reduces myocardial damage after MI. We hypothesize that a S100A9 blockade induces changes of major signaling pathways implicated in post-MI healing. Mass spectrometry-based proteomics and gene analyses of infarcted mice left ventricle were performed. The S100A9 blocker (ABR-23890) was given for 3 days after coronary ligation. At 3 and 7 days post-MI, ventricle samples were analyzed versus control and Sham-operated mice. Blockade of S100A9 modulated the expressed proteins involved in five biological processes: leukocyte cell–cell adhesion, regulation of the muscle cell apoptotic process, regulation of the intrinsic apoptotic signaling pathway, sarcomere organization and cardiac muscle hypertrophy. The blocker induced regulation of 36 proteins interacting with or targeted by the cellular tumor antigen p53, prevented myocardial compensatory hypertrophy, and reduced cardiac markers of post-ischemic stress. The blockade effect was prominent at day 7 post-MI when the quantitative features of the ventricle proteome were closer to controls. Blockade of S100A9 restores key biological processes altered post-MI. These processes could be valuable new pharmacological targets for the treatment of ischemic heart. Mass spectrometry data are available via ProteomeXchange with identifier PXD033683. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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23 pages, 4095 KiB

Open AccessArticle

VCAM-1 Targeted Lipopolyplexes as Vehicles for Efficient Delivery of shRNA-Runx2 to Osteoblast-Differentiated Valvular Interstitial Cells; Implications in Calcific Valve Disease Treatment

by Geanina Voicu, Daniela Rebleanu, Cristina Ana Mocanu, Gabriela Tanko, Ionel Droc, Cristina Mariana Uritu, Mariana Pinteala, Ileana Manduteanu, Maya Simionescu and Manuela Calin

Int. J. Mol. Sci. 2022, 23(7), 3824; https://doi.org/10.3390/ijms23073824 - 30 Mar 2022

Cited by 4 | Viewed by 2831

Abstract

Calcific aortic valve disease (CAVD) is a progressive inflammatory disorder characterized by extracellular matrix remodeling and valvular interstitial cells (VIC) osteodifferentiation leading to valve leaflets calcification and impairment movement. Runx2, the master transcription factor involved in VIC osteodifferentiation, modulates the expression of other osteogenic molecules. Previously, we have demonstrated that the osteoblastic phenotypic shift of cultured VIC is impeded by Runx2 silencing using fullerene (C60)-polyethyleneimine (PEI)/short hairpin (sh)RNA-Runx2 (shRunx2) polyplexes. Since the use of polyplexes for in vivo delivery is limited by their instability in the plasma and the non-specific tissue interactions, we designed and obtained targeted, lipid-enveloped polyplexes (lipopolyplexes) suitable for (1) systemic administration and (2) targeted delivery of shRunx2 to osteoblast-differentiated VIC (oVIC). Vascular cell adhesion molecule (VCAM)-1 expressed on the surface of oVIC was used as a target, and a peptide with high affinity for VCAM-1 was coupled to the surface of lipopolyplexes encapsulating C60-PEI/shRunx2 (V-LPP/shRunx2). We report here that V-LPP/shRunx2 lipopolyplexes are cyto- and hemo-compatible and specifically taken up by oVIC. These lipopolyplexes are functional as they downregulate the Runx2 gene and protein expression, and their uptake leads to a significant decrease in the expression of osteogenic molecules (OSP, BSP, BMP-2). These results identify V-LPP/shRunx2 as a new, appropriately directed vehicle that could be instrumental in developing novel strategies for blocking the progression of CAVD using a targeted nanomedicine approach. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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Review

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17 pages, 670 KiB

Open AccessReview

The Predictive Role of Plasma Biomarkers in the Evolution of Aortopathies Associated with Congenital Heart Malformations

by Amalia Făgărășan and Maria Oana Săsăran

Int. J. Mol. Sci. 2022, 23(9), 4993; https://doi.org/10.3390/ijms23094993 - 30 Apr 2022

Cited by 3 | Viewed by 1876

Abstract

Dilatation of the aorta is a constantly evolving condition that can lead to the ultimate life-threatening event, acute aortic dissection. Recent research has tried to identify quantifiable biomarkers, with both diagnostic and prognostic roles in different aortopathies. Most studies have focused on the bicuspid aortic valve, the most frequent congenital heart disease (CHD), and majorly evolved around matrix metalloproteinases (MMPs). Other candidate biomarkers, such as asymmetric dimethylarginine, soluble receptor for advanced glycation end-products or transforming growth factor beta have also gained a lot of attention recently. Most of the aortic anomalies and dilatation-related studies have reported expression variation of tissular biomarkers. The ultimate goal remains, though, the identification of biomarkers among the serum plasma, with the upregulation of circulating MMP-1, MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), asymmetric dimethylarginine (ADMA), soluble receptor for advanced glycation end-products (sRAGE) and transforming growth factor beta (TGF-β) being reported in association to several aortopathies and related complications in recent research. These molecules are apparently quantifiable from the early ages and have been linked to several CHDs and hereditary aortopathies. Pediatric data on the matter is still limited, and further studies are warranted to elucidate the role of plasmatic biomarkers in the long term follow-up of potentially evolving congenital aortopathies. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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15 pages, 13441 KiB

Open AccessReview

Non-Coding RNAs: Prevention, Diagnosis, and Treatment in Myocardial Ischemia–Reperfusion Injury

by Mihnea-Cosmin Marinescu, Andrada-Luciana Lazar, Monica Mihaela Marta, Angela Cozma and Cristina-Sorina Catana

Int. J. Mol. Sci. 2022, 23(5), 2728; https://doi.org/10.3390/ijms23052728 - 01 Mar 2022

Cited by 24 | Viewed by 3560

Abstract

Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia–reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients. Full article

(This article belongs to the Special Issue Molecular Research in Cardiovascular Disease 2.0)

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