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Molecular Pathways in Diabetic Cardiomyopathy

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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: closed (15 May 2023) | Viewed by 21659

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Special Issue Editor

Dr. Demetrios A. Arvanitis

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Guest Editor

Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece
Interests: cell biology; physiology; genetics; calcium, cardiomyocytes; neurons
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetic cardiomyopathy is the atherosclerosis- or hypertension independent co-morbidity of diabetes mellitus that accounts for the vast majority of diabetic complication-related mortality. The hallmark of this specific challenging form of cardiomyopathy is left ventricular hypertrophy because of cardiac remodeling associated with myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis. Diabetic cardiomyopathy appears to predominantly be a cardiomyocyte-based disease due to systematic hyperglycemia, hyperlipidemia, and insulin resistance, which produce oxidative stress in the diabetic heart. In the diabetic myocardium setting, cardiomyocytes experience mitochondrial dysfunction, endoplasmic reticulum stress, alterations in the handling of calcium ions, and significant alterations in the expression of genes and miRNAs and cell metabolism that may lead to mitophagy, autophagy, and cell death, which in turn promotes intramyocardial inflammation and increased fibrosis as the result of myocardial injury. This Special Issue of IJMS on diabetic cardiomyopathy presents novel experimental and bioinformatic research on the molecular, subcellular, cellular, tissue, and whole organ changes involved with an emphasis on the specific biochemical pathways affected, as well as reviews that summarize the existing evidence on the critical molecular players implicated in diabetic cardiomyopathy pathology. The cardioprotective potential of therapeutic anti-diabetic agents against cardiomyopathy will be discussed.

Dr. Demetrios A. Arvanitis
Guest Editor

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Keywords

diabetic cardiomyopathy
diabetes mellitus
hyperglycemia
circulating fatty acids
reactive oxygen species
cardiac myocytes
cardiac remodeling
mitochondria
endoplasmic reticulum
autophagy
renin-angiotensin system
lipotoxicity
inflammation
fibrosis
heart failure

Published Papers (7 papers)

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Research

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21 pages, 2668 KiB

Open AccessArticle

Potential Role of the mTORC1-PGC1α-PPARα Axis under Type-II Diabetes and Hypertension in the Human Heart

by Tianyu Hang, Jairo Lumpuy-Castillo, Naroa Goikoetxea-Usandizaga, Mikel Azkargorta, Gonzalo Aldámiz, Juan Martínez-Milla, Alberto Forteza, José M. Cortina, Jesús Egido, Félix Elortza, Malu Martínez-Chantar, José Tuñón and Óscar Lorenzo

Int. J. Mol. Sci. 2023, 24(10), 8629; https://doi.org/10.3390/ijms24108629 - 11 May 2023

Cited by 3 | Viewed by 2028

Abstract

Type-2 diabetes (T2DM) and arterial hypertension (HTN) are major risk factors for heart failure. Importantly, these pathologies could induce synergetic alterations in the heart, and the discovery of key common molecular signaling may suggest new targets for therapy. Intraoperative cardiac biopsies were obtained from patients with coronary heart disease and preserved systolic function, with or without HTN and/or T2DM, who underwent coronary artery bypass grafting (CABG). Control (n = 5), HTN (n = 7), and HTN + T2DM (n = 7) samples were analysed by proteomics and bioinformatics. Additionally, cultured rat cardiomyocytes were used for the analysis (protein level and activation, mRNA expression, and bioenergetic performance) of key molecular mediators under stimulation of main components of HTN and T2DM (high glucose and/or fatty acids and angiotensin-II). As results, in cardiac biopsies, we found significant alterations of 677 proteins and after filtering for non-cardiac factors, 529 and 41 were changed in HTN-T2DM and in HTN subjects, respectively, against the control. Interestingly, 81% of proteins in HTN-T2DM were distinct from HTN, while 95% from HTN were common with HTN-T2DM. In addition, 78 factors were differentially expressed in HTN-T2DM against HTN, predominantly downregulated proteins of mitochondrial respiration and lipid oxidation. Bioinformatic analyses suggested the implication of mTOR signaling and reduction of AMPK and PPARα activation, and regulation of PGC1α, fatty acid oxidation, and oxidative phosphorylation. In cultured cardiomyocytes, an excess of the palmitate activated mTORC1 complex and subsequent attenuation of PGC1α-PPARα transcription of β-oxidation and mitochondrial electron chain factors affect mitochondrial/glycolytic ATP synthesis. Silencing of PGC1α further reduced total ATP and both mitochondrial and glycolytic ATP. Thus, the coexistence of HTN and T2DM induced higher alterations in cardiac proteins than HTN. HTN-T2DM subjects exhibited a marked downregulation of mitochondrial respiration and lipid metabolism and the mTORC1-PGC1α-PPARα axis might account as a target for therapeutical strategies. Full article

(This article belongs to the Special Issue Molecular Pathways in Diabetic Cardiomyopathy)

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0 pages, 3104 KiB

Open AccessArticle

Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes

by Mostafa Samak, Andreas Kues, Diana Kaltenborn, Lina Klösener, Matthias Mietsch, Giulia Germena and Rabea Hinkel

Int. J. Mol. Sci. 2023, 24(3), 2482; https://doi.org/10.3390/ijms24032482 - 27 Jan 2023

Cited by 1 | Viewed by 1731 | Correction

Abstract

Cardiovascular complications are the main cause of morbidity and mortality from diabetes. Herein, vascular inflammation is a major pathological manifestation. We previously characterized the cardiac microvascular inflammatory phenotype in diabetic patients and highlighted micro-RNA 92a (miR-92a) as a driver of endothelial dysfunction. In this article, we further dissect the molecular underlying of these findings by addressing anti-inflammatory Krüppel-like factors 2 and 4 (KLF2 and KLF4). We show that KLF2 dysregulation in diabetes correlates with greater monocyte adhesion as well as migratory defects in cardiac microvascular endothelial cells. We also describe, for the first time, a role for myocyte enhancer factor 2D (MEF2D) in cardiac microvascular dysfunction in diabetes. We show that both KLFs 2 and 4, as well as MEF2D, are dysregulated in human and porcine models of diabetes. Furthermore, we prove a direct interaction between miR-92a and all three targets. Altogether, our data strongly qualify miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease. Full article

(This article belongs to the Special Issue Molecular Pathways in Diabetic Cardiomyopathy)

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23 pages, 6759 KiB

Open AccessArticle

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury

by Shengqi Huo, Qian Wang, Wei Shi, Lulu Peng, Yue Jiang, Mengying Zhu, Junyi Guo, Dewei Peng, Moran Wang, Lintong Men, Bingyu Huang, Jiagao Lv and Li Lin

Int. J. Mol. Sci. 2023, 24(2), 1667; https://doi.org/10.3390/ijms24021667 - 14 Jan 2023

Cited by 33 | Viewed by 7051

Abstract

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl₂ or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM. Full article

(This article belongs to the Special Issue Molecular Pathways in Diabetic Cardiomyopathy)

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Review

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13 pages, 1311 KiB

Open AccessReview

The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools

by Kuo-Li Pan, Yung-Chien Hsu, Shih-Tai Chang, Chang-Min Chung and Chun-Liang Lin

Int. J. Mol. Sci. 2023, 24(10), 8604; https://doi.org/10.3390/ijms24108604 - 11 May 2023

Cited by 10 | Viewed by 3158

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy. Full article

(This article belongs to the Special Issue Molecular Pathways in Diabetic Cardiomyopathy)

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18 pages, 2159 KiB

Open AccessReview

The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy

by Siarhei A. Dabravolski, Nikolay K. Sadykhov, Andrey G. Kartuesov, Evgeny E. Borisov, Vasily N. Sukhorukov and Alexander N. Orekhov

Int. J. Mol. Sci. 2022, 23(14), 7863; https://doi.org/10.3390/ijms23147863 - 16 Jul 2022

Cited by 17 | Viewed by 3249

Abstract

Diabetic cardiomyopathy (DCM) is defined as the presence in diabetic patients of abnormal cardiac structure and performance (such as left ventricular hypertrophy, fibrosis, and arrhythmia) in the absence of other cardiac risk factors (such as hypertension or coronary artery disease). Although the pathogenesis of DCM remains unclear currently, mitochondrial structural and functional dysfunctions are recognised as a central player in the DCM development. In this review, we focus on the role of mitochondrial dynamics, biogenesis and mitophagy, Ca²⁺ metabolism and bioenergetics in the DCM development and progression. Based on the crucial role of mitochondria in DCM, application of mitochondria-targeting therapies could be effective strategies to slow down the progression of the disease. Full article

(This article belongs to the Special Issue Molecular Pathways in Diabetic Cardiomyopathy)

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21 pages, 1832 KiB

Open AccessReview

Epigenetic Modifications and Non-Coding RNA in Diabetes-Mellitus-Induced Coronary Artery Disease: Pathophysiological Link and New Therapeutic Frontiers

by Francesca Romana Prandi, Dalgisio Lecis, Federica Illuminato, Marialucia Milite, Roberto Celotto, Stamatios Lerakis, Francesco Romeo and Francesco Barillà

Int. J. Mol. Sci. 2022, 23(9), 4589; https://doi.org/10.3390/ijms23094589 - 21 Apr 2022

Cited by 13 | Viewed by 3140

Abstract

Diabetes mellitus (DM) is a glucose metabolism disorder characterized by chronic hyperglycemia resulting from a deficit of insulin production and/or action. DM affects more than 1 in 10 adults, and it is associated with an increased risk of cardiovascular morbidity and mortality. Cardiovascular disease (CVD) accounts for two thirds of the overall deaths in diabetic patients, with coronary artery disease (CAD) and ischemic cardiomyopathy as the main contributors. Hyperglycemic damage on vascular endothelial cells leading to endothelial dysfunction represents the main initiating factor in the pathogenesis of diabetic vascular complications; however, the underlying pathophysiological mechanisms are still not entirely understood. This review addresses the current knowledge on the pathophysiological links between DM and CAD with a focus on the role of epigenetic modifications, including DNA methylation, histone modifications and noncoding RNA control. Increased knowledge of epigenetic mechanisms has contributed to the development of new pharmacological treatments (“epidrugs”) with epigenetic targets, although these approaches present several challenges. Specific epigenetic biomarkers may also be used to predict or detect the development and progression of diabetes complications. Further studies on diabetes and CAD epigenetics are needed in order to identify possible new therapeutic targets and advance personalized medicine with the prediction of individual drug responses and minimization of adverse effects. Full article

(This article belongs to the Special Issue Molecular Pathways in Diabetic Cardiomyopathy)

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