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Journal of Cachexia, Sarcopenia and... Dec 2023Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate...
BACKGROUND
Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate molecular mechanisms governing the aberrant accumulation of lipid droplets within cardiomyocytes remain to be comprehensively elucidated.
METHODS
Both obese diabetic (db/db) mice and HL-1 cells treated with 200 μmol/L palmitate and 200 μmol/L oleate were used to simulate type 2 diabetes conditions. Transmission electron microscopy is employed to assess the size and quantity of lipid droplets in the mouse hearts. Transcriptomics analysis was utilized to interrogate mRNA levels. Lipidomics and ubiquitinomics were employed to explore the lipid composition alterations and proteins participating in ubiquitin-mediated degradation in mice. Clinical data were collected from patients with diabetes-associated cardiomyopathy and healthy controls. Western blot analysis was conducted to assess the levels of proteins linked to lipid metabolism, and the biotin-switch assay was employed to quantify protein cysteine S-sulfhydration levels.
RESULTS
The administration of H S donor, NaHS, effectively restored hydrogen sulfide levels in both the cardiac tissue and plasma of db/db mice (+7%, P < 0.001; +5%, P < 0.001). Both db/db mice (+210%, P < 0.001) and diabetic patients (+83%, P = 0.22, n = 5) exhibit elevated plasma triglyceride levels. Treatment with GYY4137 effectively lowers triglyceride levels in db/db mice (-43%, P = 0.007). The expression of cystathionine gamma-lyase and HMG-CoA reductase degradation protein 1 (SYVN1) was decreased in db/db mice compared with the wild-type mice (cystathionine gamma-lyase: -31%, P = 0.0240; SYVN1: -35%, P = 0.01), and NaHS-treated mice (SYVN1: -31%, P = 0.03). Conversely, the expression of sterol regulatory element-binding protein 1 (SREBP1) was elevated (+91%, P = 0.007; +51%, P = 0.03 compared with control and NaHS-treated mice, respectively), along with diacylglycerol O-acyltransferase 1 (DGAT1) (+95%, P = 0.001; +35%, P = 0.02) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) (+88%, P = 0.01; +22%, P = 0.32). Exogenous H S led to a reduction in lipid droplet formation (-48%, P < 0.001), restoration of SYVN1 expression, modification of SYVN1's S-sulfhydration status and enhancement of SREBP1 ubiquitination. Overexpression of SYVN1 mutated at Cys115 decreased SREBP1 ubiquitination and increased the number of lipid droplets.
CONCLUSIONS
Exogenous H S enhances ubiquitin-proteasome degradation of SREBP1 and reduces its nuclear translocation by modulating SYVN1's cysteine S-sulfhydration. This pathway limits lipid droplet buildup in cardiac myocytes, ameliorating diabetic cardiomyopathy.
Topics: Animals; Humans; Mice; Cystathionine gamma-Lyase; Cysteine; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Lipids; Sterol Regulatory Element Binding Protein 1; Triglycerides; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 37899701
DOI: 10.1002/jcsm.13347 -
Current Vascular Pharmacology 2021Having in mind that diabetes mellitus (DM) and obesity are some of the greatest health challenges of the modern era, diabetic cardiomyopathy (DCM) is becoming more and...
BACKGROUND
Having in mind that diabetes mellitus (DM) and obesity are some of the greatest health challenges of the modern era, diabetic cardiomyopathy (DCM) is becoming more and more recognized in clinical practice. Main Text: Initially, DM is asymptomatic, but it may progress to diastolic and then systolic left ventricular dysfunction, which results in congestive heart failure. A basic feature of this DM complication is the absence of hemodynamically significant stenosis of the coronary blood vessels. Clinical manifestations are the result of several metabolic disorders that are present during DM progression. The complexity of metabolic processes, along with numerous regulatory mechanisms, has been the subject of research that aims at discovering new diagnostic (e.g. myocardial strain with echocardiography and cardiac magnetic resonance) and treatment options. Adequate glycaemic control is not sufficient to prevent or reduce the progression of DCM. Contemporary hypoglycemic medications, such as sodium-glucose transport protein 2 inhibitors, significantly reduce the frequency of cardiovascular complications in patients with DM. Several studies have shown that, unlike the above-stated medications, thiazolidinediones and dipeptidyl peptidase-4 inhibitors are associated with deterioration of heart failure.
CONCLUSION
Imaging procedures, especially myocardial strain with echocardiography and cardiac magnetic resonance, are useful to identify the early signs of DCM. Research and studies regarding new treatment options are still "in progress".
Topics: Diabetic Cardiomyopathies; Echocardiography; Humans; Magnetic Resonance Imaging; Myocardium
PubMed: 33143612
DOI: 10.2174/1570161119999201102213214 -
Cardiovascular & Hematological Agents... Oct 2011Diabetes has emerged as a major threat to worldwide health. The increasing incidence of diabetes in young individuals is particularly worrisome given that the disease is... (Review)
Review
Diabetes has emerged as a major threat to worldwide health. The increasing incidence of diabetes in young individuals is particularly worrisome given that the disease is likely to evolve over a period of years. In 1972, the existence of a diabetic cardiomyopathy was proposed based on the experience with four adult diabetic patients who suffered from congestive heart failure in the absence of discernible coronary artery disease, valvular or congenital heart disease, hypertension, or alcoholism. The exact mechanisms underlying the disease are unknown; however, there is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemiainduced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. In this review, we provide the emergence of experimental evidence supporting antioxidant supplementation as a cardioprotective intervention in the setting of diabetic cardiomyopathy.
Topics: Animals; Antioxidants; Cardiotonic Agents; Diabetic Cardiomyopathies; Heart; Humans; Myocardium; Oxidative Stress
PubMed: 21902660
DOI: 10.2174/187152511798120877 -
Balkan Medical Journal Sep 2023The main pathological feature of diabetic cardiomyopathy (DCM) caused by diabetes mellitus is myocardial fibrosis. According to recent studies in cardiology, it has been...
BACKGROUND
The main pathological feature of diabetic cardiomyopathy (DCM) caused by diabetes mellitus is myocardial fibrosis. According to recent studies in cardiology, it has been suggested that spermidine (SPD) has cardioprotective properties.
AIMS
To explore the role and mechanism of SPD in alleviating myocardial fibrosis of DCM.
STUDY DESIGN
In vivo and in vitro study.
METHODS
Type 2 diabetic mice and primary neonatal mouse cardiac fibroblasts (CFs) were selected. Measurements of serum-related markers, echocardiographic analysis, and immunohistochemistry were used to evaluate myocardial fibrosis injury and the effects of SPD. The proliferation and migration of CFs undergoing different treatments were studied. Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction were used to demonstrate molecular mechanisms.
RESULTS
In vivo immunoblotting analysis indicated a downregulation of ornithine decarboxylase and an upregulation of SPD/spermine N1-acetyltransferase. We observed cardiac dysfunction in diabetic mice after 12 weeks. However, the administration of exogenous SPD improved cardiac function, decreased collagen deposition, and reduced myocardial tissue damage. mRNA expression levels of NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-17A, and IL-18 were increased and suppressed in the myocardium of db/db mice upon treatment with SPD. SPD inhibited the proliferation, migration, and collagen secretion of high-glucose-treated fibroblasts in vitro. SPD inhibits the activation of the TGF-β1/Smad signaling pathway and decreases collagen deposition by reducing pyroptosis and Smad-7 ubiquitination levels.
CONCLUSION
Based on our findings, SPD may have potential applications in protecting against the deterioration of cardiac function in patients with DCM due to a significant new mechanism for diabetic myocardial fibrosis that we discovered.
Topics: Mice; Animals; Spermidine; Pyroptosis; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Collagen; Inflammation; Fibrosis
PubMed: 37350700
DOI: 10.4274/balkanmedj.galenos.2023.2023-3-102 -
Circulation. Cardiovascular Imaging Jul 2023
Topics: Humans; Diabetic Cardiomyopathies; Fibrosis; Myocardium; Cardiomyopathy, Restrictive; Diabetes Mellitus
PubMed: 37431656
DOI: 10.1161/CIRCIMAGING.123.015732 -
Cardiovascular Research Jan 2022
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Myocytes, Cardiac
PubMed: 34254135
DOI: 10.1093/cvr/cvab226 -
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 -
Heart Failure Reviews Jan 2014Chronic diabetic complications affect multiple organ systems and lead to significant morbidity and mortality in the diabetic population. Diabetic cardiomyopathy is a... (Review)
Review
Chronic diabetic complications affect multiple organ systems and lead to significant morbidity and mortality in the diabetic population. Diabetic cardiomyopathy is a major etiologic factor causing heart failure. Dysfunction of both vascular endothelial cells and cardiomyocytes contributes in the pathogenesis of diabetic cardiomyopathy. Hyperglycemia has been identified as the key determinant in the development of several chronic diabetic complications. Hyperglycemia leads to oxidative stress and several other abnormalities causing changes in cellular signaling. These diabetes-mediated biochemical anomalies show cross-interaction and complex interplay. Such changes also cause alteration of transcriptional and post-transcriptional machinery causing altered production of vasoactive and cardioactive factors. In this review, we will highlight some of the important signaling changes leading to diabetic cardiomyopathy and discuss possible potential therapeutic remedies.
Topics: Diabetic Cardiomyopathies; Glucose; Humans; Myocardium; Oxidative Stress; Signal Transduction
PubMed: 23430126
DOI: 10.1007/s10741-013-9381-z -
Arquivos Brasileiros de Cardiologia Dec 2017
Topics: Brazil; Cardiovascular Diseases; Cholesterol, LDL; Diabetic Cardiomyopathies; Evidence-Based Medicine; Humans; Hypercholesterolemia; Risk Assessment; Risk Factors; Societies, Medical
PubMed: 29489927
DOI: 10.5935/abc.20170188 -
Current Problems in Cardiology Jan 2011Diabetic heart disease is currently defined as left ventricular dysfunction that occurs independently of coronary artery disease and hypertension. Its underlying... (Review)
Review
Diabetic heart disease is currently defined as left ventricular dysfunction that occurs independently of coronary artery disease and hypertension. Its underlying etiology is likely to be multifactorial, acting synergistically together to cause myocardial dysfunction. Multimodality cardiac imaging, such as echocardiography, nuclear, computed tomography, and magnetic resonance imaging, can provide invaluable insight into different aspects of the disease process, from imaging at the cellular level for altered myocardial metabolism to microvascular and endothelial dysfunction, autonomic neuropathy, coronary atherosclerosis, and finally, interstitial fibrosis with scar formation. Furthermore, cardiac imaging is pivotal in diagnosing diabetic heart disease. Thus, the aim of the present review is to illustrate the role of multimodality cardiac imaging in elucidating the underlying pathophysiologic mechanisms of diabetic heart disease.
Topics: Cardiac Imaging Techniques; Diabetic Cardiomyopathies; Humans
PubMed: 21147361
DOI: 10.1016/j.cpcardiol.2010.10.001