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Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases 2.0

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 13742

Special Issue Editor

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

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Keywords

  • cardiovascular diseases
  • metabolic diseases
  • cellular and molecular mechanisms

Published Papers (8 papers)

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Research

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21 pages, 4751 KiB  
Article
The Elevated Inflammatory Status of Neutrophils Is Related to In-Hospital Complications in Patients with Acute Coronary Syndrome and Has Important Prognosis Value for Diabetic Patients
by Elena Barbu, Andreea Cristina Mihaila, Ana-Maria Gan, Letitia Ciortan, Razvan Daniel Macarie, Monica Madalina Tucureanu, Alexandru Filippi, Andra Ioana Stoenescu, Stefanita Victoria Petrea, Maya Simionescu, Serban Mihai Balanescu and Elena Butoi
Int. J. Mol. Sci. 2024, 25(10), 5107; https://doi.org/10.3390/ijms25105107 - 8 May 2024
Viewed by 429
Abstract
Despite neutrophil involvement in inflammation and tissue repair, little is understood about their inflammatory status in acute coronary syndrome (ACS) patients with poor outcomes. Hence, we investigated the potential correlation between neutrophil inflammatory markers and the prognosis of ACS patients with/without diabetes and [...] Read more.
Despite neutrophil involvement in inflammation and tissue repair, little is understood about their inflammatory status in acute coronary syndrome (ACS) patients with poor outcomes. Hence, we investigated the potential correlation between neutrophil inflammatory markers and the prognosis of ACS patients with/without diabetes and explored whether neutrophils demonstrate a unique inflammatory phenotype in patients experiencing an adverse in-hospital outcome. The study enrolled 229 ACS patients with or without diabetes. Poor evolution was defined as either death, left ventricular ejection fraction (LVEF) <40%, Killip Class 3/4, ventricular arrhythmias, or mechanical complications. Univariate and multivariate analyses were employed to identify clinical and paraclinical factors associated with in-hospital outcomes. Neutrophils isolated from fresh blood were investigated using qPCR, Western blot, enzymatic assay, and immunofluorescence. Poor evolution post-myocardial infarction (MI) was associated with increased number, activity, and inflammatory status of neutrophils, as indicated by significant increase of Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), fibrinogen, interleukin-1β (IL-1β), and, interleukin-6 (IL-6). Among the patients with complicated evolution, neutrophil activity had an important prognosis value for diabetics. Neutrophils from patients with unfavorable evolution revealed a pro-inflammatory phenotype with increased expression of CCL3, IL-1β, interleukin-18 (IL-18), S100A9, intracellular cell adhesion molecule-1 (ICAM-1), matrix metalloprotease (MMP-9), of molecules essential in reactive oxygen species (ROS) production p22phox and Nox2, and increased capacity to form neutrophil extracellular traps. Inflammation is associated with adverse short-term prognosis in acute ACS, and inflammatory biomarkers exhibit greater specificity in predicting short-term outcomes in diabetics. Moreover, neutrophils from patients with unfavorable evolution exhibit distinct inflammatory patterns, suggesting that alterations in the innate immune response in this subgroup may exert detrimental effects on disease progression. Full article
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11 pages, 1561 KiB  
Article
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 977
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 [...] Read more.
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
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18 pages, 5931 KiB  
Article
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 1412
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 [...] Read more.
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
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19 pages, 2394 KiB  
Article
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 1632
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 [...] Read more.
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
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16 pages, 2550 KiB  
Article
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 - 8 Mar 2023
Cited by 3 | Viewed by 1544
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 [...] Read more.
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
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17 pages, 2900 KiB  
Article
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 1666
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. [...] Read more.
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
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Review

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20 pages, 2295 KiB  
Review
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 - 7 Jan 2024
Viewed by 1674
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, [...] Read more.
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
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15 pages, 2381 KiB  
Review
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 3481
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 [...] Read more.
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
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