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Novel Molecular Targets in Cardiovascular Diseases

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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 (31 October 2021) | Viewed by 32947

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Special Issue Editors

Prof. Dr. Giulio Pompilio

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Guest Editor

Centro Cardiologico Monzino-IRCCS, Milan, Italy
Interests: cardiovascular sciences; stem cells; cardiac surgery; advanced cell models; regenerative medicine

Prof. Serena Zacchigna

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Guest Editor

Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy
Interests: angiogenesis; cardiac regeneration; gene therapy; animal models; echocardiography

Dr. Erica Rurali

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Guest Editor

Centro Cardiologico Monzino-IRCCS, Milan, Italy
Interests: cardiovascular sciences; rare diseases; vascular dysfunction; aortic aneurysm; diabetes; regenerative medicine
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Special Issue Information

Cardiovascular diseases are the leading causes of death and disability worldwide. Moreover, they represent an enormous burden for the healthcare systems of all countries. Despite any steps forward that have been made thanks to scientific and clinical research, it has been a while since novel drugs for cardiovascular diseases have been introduced into the clinical arena. Thus, the discovery of novel targets that can be exploited to develop new effective therapies is an impellent need to improve patient outcomes and limit healthcare expenses.

The Special Issue “Novel Molecular Targets in Cardiovascular Diseases” will cover a selection of the most recent scientific studies and current review articles in the field of clinical, translational, and basic research dedicated to the discovery of biomarkers, molecular, and/or cellular mechanisms to be exploited as therapeutic targets or diagnostic tools to improve the outcome of patients with cardiovascular disease. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Prof. Dr. Giulio Pompilio
Prof. Serena Zacchigna
Dr. Erica Rurali
Guest Editors

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

biomarkers (diagnostic, prognostic and predictive)
novel molecular target
cardiac disease
vascular disease
translational research
new therapies

Related Special Issue

Novel Molecular Targets in Cardiovascular Diseases 2.0 in International Journal of Molecular Sciences (6 articles)

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 181 KiB

Open AccessEditorial

Novel Targets for Old and Diseased Hearts

by Erica Rurali, Giulio Pompilio and Serena Zacchigna

Int. J. Mol. Sci. 2022, 23(12), 6627; https://doi.org/10.3390/ijms23126627 - 14 Jun 2022

Viewed by 1034

Abstract

In this Special Issue we cover a selection of original articles and reviews devoted to the definition of novel molecular targets in cardiovascular diseases, which not only deepen our knowledge on the pathogenesis of the diseases under study, but potentially pave the way [...] Read more.

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

Research

Jump to: Editorial, Review

12 pages, 2298 KiB

Open AccessArticle

Biofluid Specificity of Long Non-Coding RNA Profile in Hypertension: Relevance of Exosomal Fraction

by Angela L. Riffo-Campos, Javier Perez-Hernandez, Olga Martinez-Arroyo, Ana Ortega, Ana Flores-Chova, Josep Redon and Raquel Cortes

Int. J. Mol. Sci. 2022, 23(9), 5199; https://doi.org/10.3390/ijms23095199 - 6 May 2022

Cited by 1 | Viewed by 1956

Abstract

Non-coding RNA (ncRNA)-mediated targeting of various genes regulates the molecular mechanisms of the pathogenesis of hypertension (HTN). However, very few circulating long ncRNAs (lncRNAs) have been reported to be altered in essential HTN. The aim of our study was to identify a lncRNA profile in plasma and plasma exosomes associated with urinary albumin excretion in HTN by next-generation sequencing and to assess biological functions enriched in response to albuminuria using GO and KEGG analysis. Plasma exosomes showed higher diversity and fold change of lncRNAs than plasma, and low transcript overlapping was found between the two biofluids. Enrichment analysis identified different biological pathways regulated in plasma or exosome fraction, which were implicated in fatty acid metabolism, extracellular matrix, and mechanisms of sorting ncRNAs into exosomes, while plasma pathways were implicated in genome reorganization, interference with RNA polymerase, and as scaffolds for assembling transcriptional regulators. Our study found a biofluid specific lncRNA profile associated with albuminuria, with higher diversity in exosomal fraction, which identifies several potential targets that may be utilized to study mechanisms of albuminuria and cardiovascular damage. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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16 pages, 3348 KiB

Open AccessArticle

Exosomal and Plasma Non-Coding RNA Signature Associated with Urinary Albumin Excretion in Hypertension

by Angela L. Riffo-Campos, Javier Perez-Hernandez, Ana Ortega, Olga Martinez-Arroyo, Ana Flores-Chova, Josep Redon and Raquel Cortes

Int. J. Mol. Sci. 2022, 23(2), 823; https://doi.org/10.3390/ijms23020823 - 13 Jan 2022

Cited by 13 | Viewed by 3121

Abstract

Non-coding RNA (ncRNA), released into circulation or packaged into exosomes, plays important roles in many biological processes in the kidney. The purpose of the present study is to identify a common ncRNA signature associated with early renal damage and its related molecular pathways. Three individual libraries (plasma and urinary exosomes, and total plasma) were prepared from each hypertensive patient (with or without albuminuria) for ncRNA sequencing analysis. Next, an RNA-based transcriptional regulatory network was constructed. The three RNA biotypes with the greatest number of differentially expressed transcripts were long-ncRNA (lncRNA), microRNA (miRNA) and piwi-interacting RNA (piRNAs). We identified a common 24 ncRNA molecular signature related to hypertension-associated urinary albumin excretion, of which lncRNAs were the most representative. In addition, the transcriptional regulatory network showed five lncRNAs (LINC02614, BAALC-AS1, FAM230B, LOC100505824 and LINC01484) and the miR-301a-3p to play a significant role in network organization and targeting critical pathways regulating filtration barrier integrity and tubule reabsorption. Our study found an ncRNA profile associated with albuminuria, independent of biofluid origin (urine or plasma, circulating or in exosomes) that identifies a handful of potential targets, which may be utilized to study mechanisms of albuminuria and cardiovascular damage. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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15 pages, 2752 KiB

Open AccessArticle

Pathological Role of Phosphoglycerate Kinase 1 in Balloon Angioplasty-Induced Neointima Formation

by Chun-Hsu Pan, Yi-Chung Chien, Min-Shan Sung, Hui-Yu Huang, Ming-Jyh Sheu and Chieh-Hsi Wu

Int. J. Mol. Sci. 2021, 22(16), 8822; https://doi.org/10.3390/ijms22168822 - 17 Aug 2021

Cited by 7 | Viewed by 2473

Abstract

Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-β (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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12 pages, 1966 KiB

Open AccessArticle

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

by María N. Barrachina, Irene Izquierdo, Lidia Hermida-Nogueira, Luis A. Morán, Amparo Pérez, Ana B. Arroyo, Nuria García-Barberá, Rocío González-Conejero, Sara Troitiño, Johannes A. Eble, José Rivera, Constantino Martínez, María I. Loza, Eduardo Domínguez and Ángel García

Int. J. Mol. Sci. 2021, 22(7), 3304; https://doi.org/10.3390/ijms22073304 - 24 Mar 2021

Cited by 4 | Viewed by 2959

Abstract

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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17 pages, 2684 KiB

Open AccessArticle

Mass Spectrometry-Based Redox and Protein Profiling of Failing Human Hearts

by Tamara Tomin, Matthias Schittmayer, Simon Sedej, Heiko Bugger, Johannes Gollmer, Sophie Honeder, Barbara Darnhofer, Laura Liesinger, Andreas Zuckermann, Peter P. Rainer and Ruth Birner-Gruenberger

Int. J. Mol. Sci. 2021, 22(4), 1787; https://doi.org/10.3390/ijms22041787 - 11 Feb 2021

Cited by 8 | Viewed by 4041

Abstract

Oxidative stress contributes to detrimental functional decline of the myocardium, leading to the impairment of the antioxidative defense, dysregulation of redox signaling, and protein damage. In order to precisely dissect the changes of the myocardial redox state correlated with oxidative stress and heart failure, we subjected left-ventricular tissue specimens collected from control or failing human hearts to comprehensive mass spectrometry-based redox and quantitative proteomics, as well as glutathione status analyses. As a result, we report that failing hearts have lower glutathione to glutathione disulfide ratios and increased oxidation of a number of different proteins, including constituents of the contractile machinery as well as glycolytic enzymes. Furthermore, quantitative proteomics of failing hearts revealed a higher abundance of proteins responsible for extracellular matrix remodeling and reduced abundance of several ion transporters, corroborating contractile impairment. Similar effects were recapitulated by an in vitro cell culture model under a controlled oxygen atmosphere. Together, this study provides to our knowledge the most comprehensive report integrating analyses of protein abundance and global and peptide-level redox state in end-stage failing human hearts as well as oxygen-dependent redox and global proteome profiles of cultured human cardiomyocytes. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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14 pages, 3275 KiB

Open AccessArticle

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34⁺ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

by Yuri D’Alessandra, Mattia Chiesa, Vera Vigorelli, Veronica Ricci, Erica Rurali, Angela Raucci, Gualtiero Ivanoe Colombo, Giulio Pompilio and Maria Cristina Vinci

Int. J. Mol. Sci. 2021, 22(3), 1423; https://doi.org/10.3390/ijms22031423 - 31 Jan 2021

Cited by 5 | Viewed by 3124

Abstract

Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34⁺ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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Review

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13 pages, 1518 KiB

Open AccessReview

Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney

by Olga Martinez-Arroyo, Estela Selma-Soriano, Ana Ortega, Raquel Cortes and Josep Redon

Int. J. Mol. Sci. 2021, 22(14), 7679; https://doi.org/10.3390/ijms22147679 - 18 Jul 2021

Cited by 10 | Viewed by 6443

Abstract

Small Rab GTPases, the largest group of small monomeric GTPases, regulate vesicle trafficking in cells, which are integral to many cellular processes. Their role in neurological diseases, such as cancer and inflammation have been extensively studied, but their implication in kidney disease has not been researched in depth. Rab3a and its effector Rabphillin-3A (Rph3A) expression have been demonstrated to be present in the podocytes of normal kidneys of mice rats and humans, around vesicles contained in the foot processes, and they are overexpressed in diseases with proteinuria. In addition, the Rab3A knockout mice model induced profound cytoskeletal changes in podocytes of high glucose fed animals. Likewise, RphA interference in the Drosophila model produced structural and functional damage in nephrocytes with reduction in filtration capacities and nephrocyte number. Changes in the structure of cardiac fiber in the same RphA-interference model, open the question if Rab3A dysfunction would produce simultaneous damage in the heart and kidney cells, an attractive field that will require attention in the future. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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15 pages, 733 KiB

Open AccessReview

Cardiac Biomarkers and Autoantibodies in Endurance Athletes: Potential Similarities with Arrhythmogenic Cardiomyopathy Pathogenic Mechanisms

by Ilaria Stadiotti, Melania Lippi, Angela Serena Maione, Paolo Compagnucci, Daniele Andreini, Michela Casella, Giulio Pompilio and Elena Sommariva

Int. J. Mol. Sci. 2021, 22(12), 6500; https://doi.org/10.3390/ijms22126500 - 17 Jun 2021

Cited by 13 | Viewed by 3100

Abstract

The “Extreme Exercise Hypothesis” states that when individuals perform training beyond the ideal exercise dose, a decline in the beneficial effects of physical activity occurs. This is due to significant changes in myocardial structure and function, such as hemodynamic alterations, cardiac chamber enlargement and hypertrophy, myocardial inflammation, oxidative stress, fibrosis, and conduction changes. In addition, an increased amount of circulating biomarkers of exercise-induced damage has been reported. Although these changes are often reversible, long-lasting cardiac damage may develop after years of intense physical exercise. Since several features of the athlete’s heart overlap with arrhythmogenic cardiomyopathy (ACM), the syndrome of “exercise-induced ACM” has been postulated. Thus, the distinction between ACM and the athlete’s heart may be challenging. Recently, an autoimmune mechanism has been discovered in ACM patients linked to their characteristic junctional impairment. Since cardiac junctions are similarly impaired by intense physical activity due to the strong myocardial stretching, we propose in the present work the novel hypothesis of an autoimmune response in endurance athletes. This investigation may deepen the knowledge about the pathological remodeling and relative activated mechanisms induced by intense endurance exercise, potentially improving the early recognition of whom is actually at risk. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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17 pages, 1576 KiB

Open AccessReview

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

by Alejandro Junco-Vicente, Álvaro del Río-García, María Martín and Isabel Rodríguez

Int. J. Mol. Sci. 2021, 22(11), 5694; https://doi.org/10.3390/ijms22115694 - 27 May 2021

Cited by 16 | Viewed by 3596

Abstract

Bicuspid aortic valve (BAV) associated with aortopathy is the most common congenital heart disease in the general population. Far from being a simple harmless valve malformation, it can be a complex and heterogeneous disease and a source of chronic and acute pathology (early valvular disease, aneurysm, dissection). In the previous years, intense research has been carried out to find out and understand its mechanisms, but the pathophysiology of the disease is still not fully understood and many questions remain open. Recent studies have discovered several genetic mutations involved in the development of valvular and aortic malformations, but still cannot explain more than 5–10% of cases. Other studies have also focused on molecular alterations and cellular processes (TGF-β pathway, microRNAs, degradation of the extracellular matrix, metalloproteinases, etc.), being a field in constant search and development, looking for a therapeutic target to prevent the development of the disease. Increased knowledge about this multifaceted disorder, derived from both basic and clinical research, may influence the diagnosis, follow-up, prognosis, and therapies of affected patients in the near future. This review focuses on the latest and outstanding developments on the molecular and genetic investigations of the bicuspid aortopathy. Full article

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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