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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 10008

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Dr. Despina Sanoudou

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Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Building 15, Mikras Asias 75, 115-27 Athens, Greece
Interests: pharmacogenomics; molecular cardiology; precision medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Elizabeth Vafiadaki

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Biomedical Research Foundation, Academy of Athens, 4 Soranou Efesiou St, 115-27 Athens, Greece
Interests: cardiac cell biology; calcium homeostasis; cardiovascular physiology; cardiac disease; personalized medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular disease has been the subject of extensive research and notable advancements over the decades. However, it remains the leading cause of death, with millions affected worldwide. The available therapeutic options leave a great deal to be desired in many cases, while they remain non-existent in others. Importantly, there are many cases in which the prognosis is challenging, and response to treatment is highly variable. Even when the cause has a genetic basis, different mutations within the same gene can result in different pathophysiology, while the same gene mutation can lead to variable phenotypes. The remarkable technological advancements and scientific breakthroughs in recent years are unveiling a horizon of new possibilities. Notable examples range from in-depth omics analyses as fine as single-cell level and sophisticated artificial intelligence tools, to highly targeted gene therapy, RNAi, and CRISPR methodologies. Meanwhile, new approaches in genetic, pharmacogenetic, and nutrigenetic testing are assuming a more impactful role in caring for CVD patients.

This Special Issue focuses on cutting-edge developments in the molecular dissection of CVD disease and the development of personalized therapeutic approaches. We invite the submission of original research and review articles on the latest scientific advances toward understanding and combating CVD in the era of precision medicine.

Dr. Despina Sanoudou
Dr. Elizabeth Vafiadaki
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.

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Keywords

cardiovascular disease
personalized medicine
precision medicine
pharmacogenomics
molecular cardiology
genetic mutation
disease pathogenesis
translational research
targeted therapies

Published Papers (5 papers)

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Research

10 pages, 1506 KiB

Open AccessCommunication

Single-Cell Analysis of Contractile Forces in iPSC-Derived Cardiomyocytes: Paving the Way for Precision Medicine in Cardiovascular Disease

by Irene C. Turnbull, Apratim Bajpai, Katherine B. Jankowski and Angelo Gaitas

Int. J. Mol. Sci. 2023, 24(17), 13416; https://doi.org/10.3390/ijms241713416 - 30 Aug 2023

Cited by 1 | Viewed by 1240

Abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold enormous potential in cardiac disease modeling, drug screening, and regenerative medicine. Furthermore, patient-specific iPSC-CMS can be tested for personalized medicine. To provide a deeper understanding of the contractile force dynamics of iPSC-CMs, we employed Atomic Force Microscopy (AFM) as an advanced detection tool to distinguish the characteristics of force dynamics at a single cell level. We measured normal (vertical) and lateral (axial) force at different pacing frequencies. We found a significant correlation between normal and lateral force. We also observed a significant force–frequency relationship for both types of forces. This work represents the first demonstration of the correlation of normal and lateral force from individual iPSC-CMs. The identification of this correlation is relevant because it validates the comparison across systems and models that can only account for either normal or lateral force. These findings enhance our understanding of iPSC-CM properties, thereby paving the way for the development of therapeutic strategies in cardiovascular medicine. Full article

(This article belongs to the Special Issue Molecular Cardiology and Pharmacogenomics)

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18 pages, 7428 KiB

Open AccessArticle

Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy

by Mohit Kumar, Kobra Haghighi, Sheryl Koch, Jack Rubinstein, Francesca Stillitano, Roger J. Hajjar, Evangelia G. Kranias and Sakthivel Sadayappan

Int. J. Mol. Sci. 2023, 24(3), 2675; https://doi.org/10.3390/ijms24032675 - 31 Jan 2023

Cited by 6 | Viewed by 1998

Abstract

Phospholamban (PLN) is a major regulator of cardiac contractility, and human mutations in this gene give rise to inherited cardiomyopathies. The deletion of Arginine 14 is the most-prevalent cardiomyopathy-related mutation, and it has been linked to arrhythmogenesis and early death. Studies in PLN-humanized mutant mice indicated an increased propensity to arrhythmias, but the underlying cellular mechanisms associated with R14del-PLN cardiac dysfunction in the absence of any apparent structural remodeling remain unclear. The present study addressed the specific role of myofilaments in the setting of R14del-PLN and the long-term effects of R14del-PLN in the heart. Maximal force was depressed in skinned cardiomyocytes from both left and right ventricles, but this effect was more pronounced in the right ventricle of R14del-PLN mice. In addition, the Ca²⁺ sensitivity of myofilaments was increased in both ventricles of mutant mice. However, the depressive effects of R14del-PLN on contractile parameters could be reversed with the positive inotropic drug omecamtiv mecarbil, a myosin activator. At 12 months of age, corresponding to the mean symptomatic age of R14del-PLN patients, contractile parameters and Ca²⁺ transients were significantly depressed in the right ventricular R14del-PLN cardiomyocytes. Echocardiography did not reveal any alterations in cardiac function or remodeling, although histological and electron microscopy analyses indicated subtle alterations in mutant hearts. These findings suggest that both aberrant myocyte calcium cycling and aberrant contractility remain specific to the right ventricle in the long term. In addition, altered myofilament activity is an early characteristic of R14del-PLN mutant hearts and the positive inotropic drug omecamtiv mecarbil may be beneficial in treating R14del-PLN cardiomyopathy. Full article

(This article belongs to the Special Issue Molecular Cardiology and Pharmacogenomics)

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15 pages, 2903 KiB

Open AccessArticle

Development of a Method for the In Vivo Generation of Allogeneic Hearts in Chimeric Mouse Embryos

by Konstantina-Maria Founta, Magdalini-Ioanna Tourkodimitri, Zoi Kanaki, Sylvia Bisti and Costis Papanayotou

Int. J. Mol. Sci. 2023, 24(2), 1163; https://doi.org/10.3390/ijms24021163 - 6 Jan 2023

Viewed by 1849

Abstract

Worldwide, there is a great gap between the demand and supply of organs for transplantations. Organs generated from the patients’ cells would not only solve the problem of transplant availability but also overcome the complication of incompatibility and tissue rejection by the host immune system. One of the most promising methods tested for the production of organs in vivo is blastocyst complementation (BC). Regrettably, BC is not suitable for the creation of hearts. We have developed a novel method, induced blastocyst complementation (iBC), to surpass this shortcoming. By applying iBC, we generated chimeric mouse embryos, made up of “host” and “donor” cells. We used a specific cardiac enhancer to drive the expression of the diphtheria toxin gene (dtA) in the “host” cells, so that these cells are depleted from the developing hearts, which now consist of “donor” cells. This is a proof-of-concept study, showing that it is possible to produce allogeneic and ultimately, xenogeneic hearts in chimeric organisms. The ultimate goal is to generate, in the future, human hearts in big animals such as pigs, from the patients’ cells, for transplantations. Such a system would generate transplants in a relatively short amount of time, improving the quality of life for countless patients around the world. Full article

(This article belongs to the Special Issue Molecular Cardiology and Pharmacogenomics)

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11 pages, 1766 KiB

Open AccessArticle

The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm

by Antonio Tejera-Muñoz, Isabel Rodríguez, Álvaro Del Río-García, Yamina Mohamedi, María Martín, Valentina Chiminazzo, Beatriz Suárez-Álvarez, Carlos López-Larrea, Marta Ruiz-Ortega and Raúl R. Rodrigues-Díez

Int. J. Mol. Sci. 2022, 23(23), 15406; https://doi.org/10.3390/ijms232315406 - 6 Dec 2022

Viewed by 1590

Abstract

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-β and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30–7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development. Full article

(This article belongs to the Special Issue Molecular Cardiology and Pharmacogenomics)

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15 pages, 3406 KiB

Open AccessArticle

Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired Ca²⁺ Handling and Arrhythmogenesis

by Elizabeth Vafiadaki, Kobra Haghighi, Demetrios A. Arvanitis, Evangelia G. Kranias and Despina Sanoudou

Int. J. Mol. Sci. 2022, 23(13), 6947; https://doi.org/10.3390/ijms23136947 - 22 Jun 2022

Cited by 10 | Viewed by 2253

Abstract

Phospholamban (PLN), a key modulator of Ca²⁺-homeostasis, inhibits sarcoplasmic reticulum (SR) calcium-ATPase (SERCA2a) and regulates cardiac contractility. The human PLN mutation R14del has been identified in arrhythmogenic cardiomyopathy patients worldwide and is currently extensively investigated. In search of the molecular mechanisms mediating the pathological phenotype, we examined PLN-R14del associations to known PLN-interacting partners. We determined that PLN-R14del interactions to key Ca²⁺-handling proteins SERCA2a and HS-1-associated protein X-1 (HAX-1) were enhanced, indicating the super-inhibition of SERCA2a’s Ca²⁺-affinity. Additionally, histidine-rich calcium binding protein (HRC) binding to SERCA2a was increased, suggesting the inhibition of SERCA2a maximal velocity. As phosphorylation relieves the inhibitory effect of PLN on SERCA2a activity, we examined the impact of phosphorylation on the PLN-R14del/SERCA2a interaction. Contrary to PLN-WT, phosphorylation did not affect PLN-R14del binding to SERCA2a, due to a lack of Ser-16 phosphorylation in PLN-R14del. No changes were observed in the subcellular distribution of PLN-R14del or its co-localization to SERCA2a. However, in silico predictions suggest structural perturbations in PLN-R14del that could impact its binding and function. Our findings reveal for the first time that by increased binding to SERCA2a and HAX-1, PLN-R14del acts as an enhanced inhibitor of SERCA2a, causing a cascade of molecular events contributing to impaired Ca²⁺-homeostasis and arrhythmogenesis. Relieving SERCA2a super-inhibition could offer a promising therapeutic approach for PLN-R14del patients. Full article

(This article belongs to the Special Issue Molecular Cardiology and Pharmacogenomics)

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