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International Journal of Molecular... Jul 2019The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized... (Review)
Review
The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) and it can account for 15-20% of the total diabetic population. The pathogenesis of DCM remains controversial, and several molecular and cellular alterations including myocardial hypertrophy, interstitial fibrosis, oxidative stress and vascular inflammation, have been postulated. The main cardio-vascular alterations associated with hyperglycemia comprise endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation. High glucose concentrations lead to a loss of mitochondrial networks, increased reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) activation and a reduction in cGMP production related to protein kinase G (PKG) activity. Current mechanisms enhance the collagen deposition with subsequent increased myocardial stiffness. Several concerns regarding the exact role of DCM in HF development such as having an appearance as either dilated or as a concentric phenotype and whether diabetes could be considered a causal factor or a comorbidity in HF, remain to be clarified. In this review, we sought to explain the different DCM subtypes and the underlying pathophysiological mechanisms. Therefore, the traditional and new molecular and signal alterations and their relationship with macroscopic structural abnormalities are described.
Topics: Animals; Diabetic Cardiomyopathies; Gene Expression Regulation; Glycation End Products, Advanced; Humans; Hyperglycemia; Inflammation; MicroRNAs; Myocardium; Oxidative Stress
PubMed: 31269778
DOI: 10.3390/ijms20133264 -
Experimental and Clinical Endocrinology... Dec 2019
Review
Topics: Atrial Fibrillation; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans
PubMed: 31860930
DOI: 10.1055/a-1018-9065 -
Antioxidants & Redox Signaling Jun 2015Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand.... (Review)
Review
SIGNIFICANCE
Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca(2+) handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression.
RECENT ADVANCES
Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM.
CRITICAL ISSUES
Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear.
FUTURE DIRECTIONS
Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction.
Topics: Animals; Diabetic Cardiomyopathies; Energy Metabolism; Humans; Mitochondria; Mitochondrial Dynamics; Myocardium; Reactive Oxygen Species
PubMed: 25738230
DOI: 10.1089/ars.2015.6293 -
International Journal of Molecular... May 2023Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular... (Review)
Review
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.
Topics: Humans; Diabetic Cardiomyopathies; Heart Failure; Stroke Volume; Fibrosis; Hyperglycemia; Diabetes Mellitus
PubMed: 37239956
DOI: 10.3390/ijms24108604 -
Cardiovascular Diabetology Oct 2023The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to...
BACKGROUND
The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.
METHODS
To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.
RESULTS
Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.
CONCLUSION
CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.
Topics: Animals; Mice; Adenosine Triphosphate; Diabetes Mellitus; Diabetic Cardiomyopathies; Energy Metabolism; Insulin; Mice, Transgenic; Mitochondria, Heart; Myocardium; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 37891673
DOI: 10.1186/s12933-023-02020-1 -
Experimental Diabetes Research 2012The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated... (Review)
Review
The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated functions results in an evolutionarily conserved cell stress response, the unfolded protein response (UPR) that is also called ER stress. ER stress is aimed initially at compensating for damage but can eventually trigger cell death if ER stress is excessive or prolonged. Now the ER stress has been associated with numerous diseases. For instance, our recent studies have demonstrated the important role of ER stress in diabetes-induced cardiac cell death. It is known that apoptosis has been considered to play a critical role in diabetic cardiomyopathy. Therefore, this paper will summarize the information from the literature and our own studies to focus on the pathological role of ER stress in the development of diabetic cardiomyopathy. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in diabetic cardiomyopathy will provide us with new targets for drug discovery and therapeutic intervention.
Topics: Animals; Diabetic Cardiomyopathies; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heart; Homeostasis; Humans; Models, Biological; Myocardium; Unfolded Protein Response
PubMed: 22144992
DOI: 10.1155/2012/827971 -
Metabolism: Clinical and Experimental May 2016Type II diabetes mellitus (DM) is a common comorbidity in patients with cardiovascular disease (CVD). Epidemiological studies including the Framingham, UKPDS, and MRFIT... (Review)
Review
Type II diabetes mellitus (DM) is a common comorbidity in patients with cardiovascular disease (CVD). Epidemiological studies including the Framingham, UKPDS, and MRFIT studies have shown diabetes to be an independent risk factor for cardiovascular disease associated with increased incidence of morbidity and mortality. However, major randomized controlled clinical trials including ADVANCE, VAD, and ACCORD have failed to demonstrate a significant reduction in CVD complications from longstanding DM with strict glycemic control. This suggests that despite the strong clinical correlation between DM and CVD, the precise mechanisms of DM-mediated CVD pathogenesis remain unclear. Signal transduction investigations have shed some light on this question with numerous studies demonstrating the role of kinase pathways in facilitating DM and CVD pathology. Abnormalities in endothelial, vascular smooth muscle, and myocardial function from the pathological insults of hyperglycemia and oxidative stress in diabetes are thought to accelerate the development of cardiovascular disease. Extensive interplay between kinase pathways that regulate the complex pathology of DM-mediated CVD is heavily regulated by a number of post-translational modifications (PTMs). In this review, we focus on the role of a dynamic PTM known as SUMOylation and its role in regulating these kinase networks to provide a mechanistic link between DM and CVD.
Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Endothelium, Vascular; Humans; Models, Cardiovascular; Protein Kinases; Signal Transduction; Sumoylation; Vasculitis
PubMed: 27085771
DOI: 10.1016/j.metabol.2016.01.007 -
Oxidative Medicine and Cellular... 2022As a serious cardiovascular complication, diabetic cardiomyopathy (DCM) refers to diabetes-related changes in myocardial structure and function, which is obviously... (Review)
Review
As a serious cardiovascular complication, diabetic cardiomyopathy (DCM) refers to diabetes-related changes in myocardial structure and function, which is obviously different from those cardiomyopathy secondary to hypertension, coronary heart disease, and valvular disease. The clinical features of DCM are left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. DCM will lead to cardiac dysfunction, eventually progress to cardiac arrhythmia, heart failure, and sudden cardiac death. At present, the pathogenesis of DCM is complex and not fully elucidated, and oxidative stress (OS), inflammatory response, glucolipid metabolism disorder, etc., are considered as the potential pathophysiological mechanisms. As a consequence, there is no specific and effective treatment for DCM. OS refers to the imbalance between reactive oxygen species (ROS) accumulation and scavenging, oxidation, and antioxidants in vivo, which is widely studied in DCM. Numerous studies have pointed out that regulating the OS signaling pathways and reducing the generation and accumulation of ROS are potential directions for the treatment of DCM. This review summarizes the major OS signaling pathways that are related to the pathogenesis of DCM, providing ideas about further research and therapy.
Topics: Diabetes Complications; Diabetic Cardiomyopathies; Humans; NF-kappa B; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Sirtuin 1
PubMed: 35103095
DOI: 10.1155/2022/5913374 -
Frontiers in Endocrinology 2021The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated... (Review)
Review
The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated morbidity and mortality; therefore, a comprehensive understanding of DCM development is required for more effective treatment. A disorder of epigenetic posttranscriptional modification of histones in chromatin has been reported to be associated with the pathology of DCM. Recent studies have implicated that histone deacetylases could regulate cardiovascular and metabolic diseases in cellular processes including cardiac fibrosis, hypertrophy, oxidative stress and inflammation. Therefore in this review, we summarized the roles of histone deacetylases in the pathogenesis of DCM, aiming to provide insights into exploring potential preventative and therapeutic strategies of DCM.
Topics: Diabetic Cardiomyopathies; Epigenesis, Genetic; Histone Deacetylases; Humans; Myocardium; Oxidative Stress
PubMed: 34367065
DOI: 10.3389/fendo.2021.679655 -
Journal of Diabetes Research 2017Although ischemic heart disease is the major cause of death in diabetic patients, diabetic cardiomyopathy (DCM) is increasingly recognized as a clinically relevant... (Review)
Review
Although ischemic heart disease is the major cause of death in diabetic patients, diabetic cardiomyopathy (DCM) is increasingly recognized as a clinically relevant entity. Considering that it comprises a variety of mechanisms and effects on cardiac function, increasing the risk of heart failure and worsening the prognosis of this patient category, DCM represents an important complication of diabetes mellitus, with a silent development in its earlier stages, involving intricate pathophysiological mechanisms, including oxidative stress, defective calcium handling, altered mitochondrial function, remodeling of the extracellular matrix, and consequent deficient cardiomyocyte contractility. While DCM is common in diabetic asymptomatic patients, it is frequently underdiagnosed, due to few diagnostic possibilities in its early stages. Moreover, since a strategy for prevention and treatment in order to improve the prognosis of DCM has not been established, it is important to identify clear pathophysiological landmarks, to pinpoint the available diagnostic possibilities and to spot potential therapeutic targets.
Topics: Calcium; Diabetic Cardiomyopathies; Diastole; Echocardiography, Doppler; Exercise Test; Fatty Acids, Nonesterified; Humans; Magnetic Resonance Spectroscopy; MicroRNAs; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Ubiquitination; Ventricular Dysfunction, Left
PubMed: 28421204
DOI: 10.1155/2017/1310265