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Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 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 Endocrinology and Metabolism".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 12466

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Special Issue Editor

Dr. Paramjit S. Tappia

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Guest Editor

Asper Clinical Research Institute, St. Boniface Hospital, Winnipeg, MB R2H 2A6, Canada
Interests: cardiovascular disease; diabetes; nutrition; early-stage lung cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue, “Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases”.

Cardiovascular and metabolic diseases, including obesity and diabetes, are major global health hazards that also represent increasing human and economic burdens. However, the underlying cellular and molecular processes that cause these abnormalities are not fully understood. Therefore, a complete understanding of the cellular and molecular mechanisms involved in the development of cardiovascular and metabolic diseases could help in the introduction of novel strategies for an improved reduction in the risk/predisposition of such diseases in the vulnerable and at-risk populations as well as better-quality treatment. It is envisioned that this Special Issue will bring together contributions from experts around the world to describe recent advances in the different mechanisms that lead to the development of cardiovascular and metabolic diseases. This Special Issue will be uniquely positioned, as it will focus on the cellular and molecular mechanisms of cardiovascular disease as well as metabolic diseases including obesity and diabetes. Since cardiovascular and metabolic diseases are linked and can occur concomitantly, an interplay or overlapping of some mechanisms may exist between these pathophysiological conditions, which may be of scientific interest. Overall, the information provided in this Special Issue will be of value in the design of novel therapeutic interventions to reduce or reverse cardiovascular and metabolic diseases as well as assist in establishing improved approaches for their prevention.

Dr. Paramjit S. Tappia
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

cardiovascular diseases
metabolic diseases
cellular and molecular mechanisms

Published Papers (7 papers)

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Research

Jump to: Review

11 pages, 1561 KiB

Open AccessArticle

Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation

by Elsa Villa-Fernández, Ana Victoria García, Alejandra Fernández-Fernández, Miguel García-Villarino, Jessica Ares-Blanco, Pedro Pujante, Tomás González-Vidal, Mario F. Fraga, Edelmiro Menéndez Torre, Elias Delgado and Carmen Lambert

Int. J. Mol. Sci. 2024, 25(5), 2637; https://doi.org/10.3390/ijms25052637 - 24 Feb 2024

Viewed by 864

Abstract

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin’s are being analysed. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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18 pages, 5931 KiB

Open AccessArticle

The Functional Role of Myogenin in Cardiomyoblast H9c2 Cells Treated with High Glucose and Palmitic Acid: Insights into No-Rejection Heart Transplantation

by Po-Shun Hsu, Shu-Ting Liu, Yi-Lin Chiu and Chien-Sung Tsai

Int. J. Mol. Sci. 2023, 24(17), 13031; https://doi.org/10.3390/ijms241713031 - 22 Aug 2023

Viewed by 1326

Abstract

Various pathological alterations, including lipid-deposition-induced comparative cardiac lipotoxicity, contribute to cardiac aging in the failing heart. A decline in endogenous myogenin proteins can lead to the reversal of muscle cell differentiation and the creation of mononucleated muscle cells. Myogenin may be a specific regulator of adaptive responses to avoid pathological hypertrophy in the heart. Hence, it is important to understand the regulation of myogenin expression and functions in response to exposure to varied stresses. In this study, we first examined and verified the cytotoxic effect of palmitic acid on H9c2 cells. The reduction in myogenin mRNA and protein expression by palmitic acid was independent of the effect of glucose. Meanwhile, the induction of cyclooxygenase 2 and activating transcription factor 3 mRNAs and proteins by palmitic acid was dependent on the presence of glucose. In addition, palmitic acid failed to disrupt cell cycle progression when H9c2 cells were treated with no glucose. Next, we examined the functional role of myogenin in palmitic-acid-treated H9c2 cells and found that myogenin may be involved in palmitic-acid-induced mitochondrial and cytosolic ROS generation, cellular senescence, and mitochondrial membrane potential. Finally, the GSE150059 dataset was deposited in the Gene Expression Omnibus website and the dataset was further analyzed via the molecular microscope diagnostic system (MMDx), demonstrating that many heart transplant biopsies currently diagnosed as no rejection have mild molecular-antibody-mediated rejection-related changes. Our data show that the expression levels of myogenin were lower than the average level in the studied population. Combining these results, we uncover part of the functional role of myogenin in lipid- and glucose-induced cardiac cell stresses. This finding provides valuable insight into the differential role of fatty-acid-associated gene expression in cardiovascular tissues. Additionally, the question of whether this gene expression is regulated by myogenin also highlights the usefulness of a platform such as MMDx-Heart and can help elucidate the functional role of myogenin in heart transplantation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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19 pages, 2394 KiB

Open AccessArticle

Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria

by Miriam Longo, Daniel Jericó, Karol M. Córdoba, José Ignacio Riezu-Boj, Raquel Urtasun, Isabel Solares, Ana Sampedro, María Collantes, Ivan Peñuelas, María Jesús Moreno-Aliaga, Matías A. Ávila, Elena Di Pierro, Miguel Barajas, Fermín I. Milagro, Paola Dongiovanni and Antonio Fontanellas

Int. J. Mol. Sci. 2023, 24(15), 11938; https://doi.org/10.3390/ijms241511938 - 26 Jul 2023

Viewed by 1523

Abstract

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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16 pages, 2550 KiB

Open AccessArticle

Cardiac Hamp mRNA Is Predominantly Expressed in the Right Atrium and Does Not Respond to Iron

by Maria Bigorra Mir, Edouard Charlebois, Sofiya Tsyplenkova, Carine Fillebeen and Kostas Pantopoulos

Int. J. Mol. Sci. 2023, 24(6), 5163; https://doi.org/10.3390/ijms24065163 - 08 Mar 2023

Cited by 2 | Viewed by 1477

Abstract

Hepcidin is a liver-derived hormone that controls systemic iron traffic. It is also expressed in the heart, where it acts locally. We utilized cell and mouse models to study the regulation, expression, and function of cardiac hepcidin. Hepcidin-encoding Hamp mRNA was induced upon differentiation of C2C12 cells to a cardiomyocyte-like phenotype and was not further stimulated by BMP6, BMP2, or IL-6, the major inducers of hepatic hepcidin. The mRNAs encoding hepcidin and its upstream regulator hemojuvelin (Hjv) are primarily expressed in the atria of the heart, with ~20-fold higher Hamp mRNA levels in the right vs. left atrium and negligible expression in the ventricles and apex. Hjv^−/− mice, a model of hemochromatosis due to suppression of liver hepcidin, exhibit only modest cardiac Hamp deficiency and minor cardiac dysfunction. Dietary iron manipulations did not significantly affect cardiac Hamp mRNA in the atria of wild-type or Hjv^−/− mice. Two weeks following myocardial infarction, Hamp was robustly induced in the liver and heart apex but not atria, possibly in response to inflammation. We conclude that cardiac Hamp is predominantly expressed in the right atrium and is partially regulated by Hjv; however, it does not respond to iron and other inducers of hepatic hepcidin. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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17 pages, 2900 KiB

Open AccessArticle

Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat

by Chana Yagil, Ronen Varadi-Levi, Chen Ifrach and Yoram Yagil

Int. J. Mol. Sci. 2023, 24(2), 1355; https://doi.org/10.3390/ijms24021355 - 10 Jan 2023

Cited by 3 | Viewed by 1597

Abstract

The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhancing ER stress, and preventing CDs/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs/y and CDr/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr/y but not in CDs/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2α, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs/y RD, insulin secretion was mildly impaired, whereas in CDs/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent Ndufa4 mutation, are highly likely to contribute to the pathophysiology of diabetes in this model. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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Review

Jump to: Research

20 pages, 2295 KiB

Open AccessReview

Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old

by Antonio Curcio, Rosa Scalise and Ciro Indolfi

Int. J. Mol. Sci. 2024, 25(2), 758; https://doi.org/10.3390/ijms25020758 - 07 Jan 2024

Viewed by 1509

Abstract

Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients’ survival rate. Due to empowered diagnostics, it has become increasingly recognized among young individuals as well, in whom it is influenced by a complex interplay of autoimmune, inflammatory, and electrophysiological mechanisms. Deepening our understanding of these mechanisms could contribute to improving AF management and treatment. Inflammation is a complexly regulated process, with interactions among various immune cell types, signaling molecules, and complement components. Addressing circulating antibodies and designing specific autoantibodies are promising therapeutic options. In cardiomyopathies or channelopathies, the first manifestation could be paroxysmal AF; persistent forms tend not to respond to antiarrhythmic drugs in these conditions. Further research, both in vitro and in vivo, on the use of genomic biotechnology could lead to new therapeutic approaches. Additional triggers that can be encountered in AF patients below 60 years of age are systemic hypertension, overweight, diabetes, and alcohol abuse. The aims of this review are to briefly report evidence from basic science and results of clinical studies that might explain the juvenile burden of the most encountered sustained supraventricular tachyarrhythmias in the general population. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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15 pages, 2381 KiB

Open AccessReview

Human Endogenous Retrovirus, SARS-CoV-2, and HIV Promote PAH via Inflammation and Growth Stimulation

by Desheng Wang, Marta T. Gomes, Yanfei Mo, Clare C. Prohaska, Lu Zhang, Sarvesh Chelvanambi, Matthias A. Clauss, Dongfang Zhang, Roberto F. Machado, Mingqi Gao and Yang Bai

Int. J. Mol. Sci. 2023, 24(8), 7472; https://doi.org/10.3390/ijms24087472 - 18 Apr 2023

Cited by 3 | Viewed by 3336

Abstract

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures. It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause PAH, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human endogenous retrovirus K(HERV-K), and human immunodeficiency virus (HIV), in part due to acute and chronic inflammation. In this review, we discuss the connections between HERV-K, HIV, SARS-CoV-2, and PAH, to stimulate research regarding new therapeutic options and provide new targets for the treatment of the disease. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0)

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