-
Cardiovascular Research Jan 2022The aim of this study was to identify the molecular mechanism for hyperglycaemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance...
AIMS
The aim of this study was to identify the molecular mechanism for hyperglycaemia-induced metabolic memory in endothelial cells (ECs), and to show its critical importance to development of cardiovascular dysfunction in diabetes.
METHODS AND RESULTS
Hyperglycaemia induces increased nuclear factor-κB (NF-κB) signalling, up-regulation of miR-27a-3p, down-regulation of nuclear factor erythroid-2 related factor 2 (NRF2) expression, increased transforming growth factor-β (TGF-β) signalling, down-regulation of miR-29, and induction of endothelial-to-mesenchymal transition (EndMT), all of which are memorized by ECs and not erased when switched to a low glucose condition, thereby causing perivascular fibrosis and cardiac dysfunction. Similar metabolic memory effects are found for production of nitric oxide (NO), generation of reactive oxygen species (ROS), and the mitochondrial oxygen consumption rate in two different types of ECs. The observed metabolic memory effects in ECs are blocked by NRF2 activator tert-butylhydroquinone and a miR-27a-3p inhibitor. In vivo, the NRF2 activator and miR-27a-3p inhibitor block cardiac perivascular fibrosis and restore cardiovascular function by decreasing NF-κB signalling, down-regulating miR-27a-3p, up-regulating NRF2 expression, reducing TGF-β signalling, and inhibiting EndMT during insulin treatment of diabetes in streptozotocin-induced diabetic mice, whereas insulin alone does not improve cardiac function.
CONCLUSIONS
Our data indicate that disruption of hyperglycaemia-induced EC metabolic memory is required for restoring cardiac function during treatment of diabetes, and identify a novel molecular signalling pathway of NF-κB/miR-27a-3p/NRF2/ROS/TGF-β/EndMT involved in metabolic memory.
Topics: Animals; Blood Glucose; Cells, Cultured; Diabetic Cardiomyopathies; Disease Models, Animal; Endothelial Cells; Energy Metabolism; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Hydroquinones; Male; Mice, Inbred BALB C; MicroRNAs; NF-E2-Related Factor 2; NF-kappa B; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta; Mice
PubMed: 33483741
DOI: 10.1093/cvr/cvab013 -
Circulation Research May 2020The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to,... (Review)
Review
The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to, well-established cardiovascular risk factors. A key contributor to this abnormal structural-functional relation is the complex interplay of myocardial metabolic remodeling, defined as the loss the flexibility in myocardial substrate metabolism and its downstream detrimental effects, such as mitochondrial dysfunction, inflammation, and fibrosis. In parallel with the growth in understanding of these biological underpinnings has been developmental advances in imaging tools such as positron emission tomography and magnetic resonance imaging and spectroscopy that permit the detection and in many cases quantification, of the processes that typifies the myocardial metabolic remodeling in diabetic cardiomyopathy. The imaging readouts can be obtained in both preclinical models of diabetes mellitus and patients with diabetes mellitus facilitating the bi-directional movement of information between bench and bedside. Moreover, imaging biomarkers provided by these tools are now being used to enhance discovery and development of therapies designed to reduce the myocardial effects of diabetes mellitus through metabolic modulation. In this review, the use of these imaging tools in the patient with diabetes mellitus from a mechanistic, therapeutic effect, and clinical management perspective will be discussed.
Topics: Animals; Diabetic Cardiomyopathies; Energy Metabolism; Fibrosis; Humans; Inflammation; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 32437305
DOI: 10.1161/CIRCRESAHA.120.315899 -
International Journal of Molecular... Dec 2021Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating... (Review)
Review
Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating innate immune and inflammatory responses. However, the mechanisms initiating and promoting NLRP3 inflammasome activation in DCM is largely unexplored. The aim of the present review is to describe the link between NLRP3 inflammasome and DCM, and to provide evidence highlighting the importance of exercise training in DCM intervention. Collectively, this evidence suggests that DCM is an inflammatory disease aggravated by NLRP3 inflammasome-mediated release of IL-1β and IL-18. In addition, chronic exercise intervention is an effective preventive and therapeutic method to alleviate DCM via modulating the NLRP3 inflammasome.
Topics: Diabetic Cardiomyopathies; Exercise Therapy; Gene Expression Regulation; Humans; Interleukin-18; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Treatment Outcome
PubMed: 34948026
DOI: 10.3390/ijms222413228 -
Cell Stress & Chaperones Nov 2023Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension.... (Review)
Review
Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.
Topics: Humans; Diabetic Cardiomyopathies; Mitochondria; Myocytes, Cardiac; Myocardial Ischemia; Cardiovascular Diseases; Mitochondrial Dynamics; Diabetes Mellitus
PubMed: 37405612
DOI: 10.1007/s12192-023-01361-w -
Biochemical Pharmacology Aug 2023Transient receptor potential ankyrin 1 (TRPA1) has been linked to the development of various cardiovascular diseases, but its role in diabetic cardiomyopathy is not well...
BACKGROUND
Transient receptor potential ankyrin 1 (TRPA1) has been linked to the development of various cardiovascular diseases, but its role in diabetic cardiomyopathy is not well understood. This study aimed to investigate the protective effects of TRPA1 deficiency on diabetic cardiomyopathy in rats with streptozotocin-induced diabetes and in neonatal rat cardiac fibroblasts (CFs) exposed to high glucose (HG).
METHODS
Cardiac TRPA1 expression levels were measured in diabetic rats. Cardiac function, remodeling, and fibrosis were analyzed in Sprague-Dawley (SD) rats and TRPA1-deficient rats with diabetic cardiomyopathy. In vitro, fibrosis was measured in CFs exposed to HG. Additionally, 1,8-cineole, a natural inhibitor of TRPA1, was used to treat SD rats with diabetic cardiomyopathy.
RESULTS
TRPA1 expression was increased in the heart tissue of diabetic rats and in CFs treated with HG. TRPA1 deficiency significantly improved cardiac function in diabetic rats, as evidenced by improved echocardiography and reduced cardiac hypertrophy and fibrosis. In vitro, TRPA1 deficiency suppressed the transformation of HG-induced CFs into myofibroblasts. The cardioprotective effect of TRPA1 deficiency was found to inhibit cardiac fibrosis by regulating GRK5/NFAT signaling. Furthermore, inhibition of GRK5/NFAT signaling abolished the promotion of CF transformation into myofibroblasts by TRPA1 activation. Inhibition of TRPA1 activation by 1,8-cineole reduced cardiac dysfunction and remodeling in diabetic rats by regulating GRK5/NFAT signaling.
CONCLUSIONS
TRPA1 deficiency reduced cardiac fibrosis in diabetic rats and inhibited HG-induced CF activation in vitro by regulating GRK5/NFAT signaling. The TRPA1 inhibitor 1,8-cineole may serve as a novel therapeutic agent for the treatment of diabetic cardiomyopathy.
Topics: Rats; Animals; Diabetic Cardiomyopathies; Diabetes Mellitus, Experimental; Rats, Sprague-Dawley; Eucalyptol; Fibrosis
PubMed: 37380112
DOI: 10.1016/j.bcp.2023.115671 -
Biochimica Et Biophysica Acta.... Jan 2021Diabetes mellitus-induced heart disease, including diabetic cardiomyopathy, is an important medical problem and is difficult to treat. Diabetes mellitus increases the... (Review)
Review
Diabetes mellitus-induced heart disease, including diabetic cardiomyopathy, is an important medical problem and is difficult to treat. Diabetes mellitus increases the risk for heart failure and decreases cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium concentration ([Ca]) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate the activity of key mitochondrial dehydrogenases. The mitochondrial calcium uniporter complex (MCUC) plays a major role in mediating mitochondrial Ca import, and its expression and function therefore may have a marked impact on cardiac myocyte metabolism and function. Here, we summarize the pathophysiological role of [Ca] handling and MCUC in the diabetic heart. In addition, we evaluate potential therapeutic targets, directed to the machinery that regulates mitochondrial calcium handling, to alleviate diabetes-related cardiac disease.
Topics: Calcium Channels; Calcium Signaling; Diabetic Cardiomyopathies; Humans; Mitochondria, Heart; Myocytes, Cardiac
PubMed: 33002576
DOI: 10.1016/j.bbadis.2020.165984 -
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 -
Heart Failure Reviews Jan 2020The presence of comorbidities significantly influences long-term morbidity and mortality of symptomatic and asymptomatic heart failure (HF) patients. Metabolic syndrome... (Review)
Review
The presence of comorbidities significantly influences long-term morbidity and mortality of symptomatic and asymptomatic heart failure (HF) patients. Metabolic syndrome and diabetic cardiomyopathy are two clinical conditions that share multiple pathophysiological mechanisms and that might be both responsible for cardiac dysfunction. However, it is argued whether metabolic syndrome (MS) independently increases HF risk or the association between MS and HF merely reflects the impact of individual risk factors included in its definition on HF development. Similarly, in the context of diabetic cardiomyopathy, many aspects are still challenging starting from the definition up to the therapeutic management. In this clinical review, we focused the attention on molecular pathways, myocyte alterations, and specific patterns of metabolic syndrome and diabetic cardiomyopathy in order to better define the potential diagnostic and therapeutic approaches of these two pathological conditions.
Topics: Diabetic Cardiomyopathies; Heart Failure; Humans; Insulin Resistance; Metabolic Syndrome
PubMed: 31414215
DOI: 10.1007/s10741-019-09838-6 -
Current Hypertension Reviews 2021The relationship between diabetes and risk of heart failure has been described in previous trials, releasing the importance of the hyperglycemic state that, added to... (Review)
Review
The relationship between diabetes and risk of heart failure has been described in previous trials, releasing the importance of the hyperglycemic state that, added to other risk factors, favors the development of coronary heart disease. The mechanism by which, in the absence of hypertension, obesity and/or dyslipidemia, diabetic patients develop cardiomyopathy has been less studied. Recently, the Sodium Glucose Co-transporter type 2 inhibitors (SGLT2 inhibitors) used for the treatment of heart failure patients with or without diabetes has been a breakthrough in the field of medicine. This review describes the established pathophysiology of diabetic cardiomyopathy and SGLT2 inhibitors, their mechanisms of action, and benefits in this group of patients.
Topics: Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 33823781
DOI: 10.2174/1573402117666210406111927 -
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