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Biochimica Et Biophysica Acta.... Feb 2024Secreted frizzled-related protein 2 (SFRP2), a novel adipokine that used to be considered an inhibitor of the canonical Wnt pathway, may play a protective role in...
OBJECTIVES
Secreted frizzled-related protein 2 (SFRP2), a novel adipokine that used to be considered an inhibitor of the canonical Wnt pathway, may play a protective role in metabolic disorders. However, its effect on diabetic cardiomyopathy was still unclear. Accumulating evidence indicates that mitophagy can protect cardiac function in the diabetic heart. The present study aimed to explore the roles of SFRP2 on diabetic cardiomyopathy, focusing on the effects and mechanisms for regulating mitophagy.
METHODS
Wild-type H9c2 cells, Sfrp2 overexpression and knockdown H9c2 cells were exposed to a glucolipotoxic milieu. Reactive oxygen species (ROS) production, cell viability, apoptosis, mitophagy and lysosomal activity were detected. The interaction of SFRP2 with frizzled 5 (FZD5), and its effect on expression and intracellular localization of transcription factor EB (TFEB) and β-catenin were also explored. Diabetic rats and Sfrp2 overexpression diabetic rats were constructed to further document the findings from the in vitro study.
RESULTS
The expression of SFRP2 was low and mitophagy was inhibited in H9c2 cells in a glucolipotoxic milieu. Sfrp2 overexpression activated mitophagy and reduced H9c2 cells injury, whereas Sfrp2 deficiency inhibited mitophagy and worsened this injury. Consistent with the in vitro findings, Sfrp2 overexpression ameliorated the impairment in cardiac function of diabetic rats by activating mitophagy. Sfrp2 overexpression upregulated the expression of calcineurin and TFEB, but did not affect β-catenin in vitro and in vivo. The calcineurin inhibitor tacrolimus can inhibit mitophagy and worsen cell injury in Sfrp2 overexpression H9c2 cells. Furthermore, we found that FZD5 is required for the SFRP2-induced activation of the calcineurin/TFEB pathway and interacts with SFRP2 in H9c2 cells. Transfection with small interfering RNA targeting FZD5 opposed the effects of Sfrp2 overexpression on mitophagy and cell survival in a glucolipotoxic environment.
CONCLUSIONS
SFRP2 can protect the diabetic heart by interacting with FZD5 and activating the calcineurin/TFEB pathway to upregulate mitophagy in H9c2 cells.
Topics: Rats; Animals; beta Catenin; Secreted Frizzled-Related Proteins; Mitophagy; Diabetic Cardiomyopathies; Diabetes Mellitus, Experimental; Calcineurin; Membrane Proteins
PubMed: 38101654
DOI: 10.1016/j.bbadis.2023.166989 -
International Journal of Molecular... Nov 2023Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by...
Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD in mammals, plays an important role in various cardiovascular diseases, according to our previous studies. However, the role of CD38 in diabetes-induced cardiomyopathy is still unknown. Here, we report that global deletion of the CD38 gene significantly prevented diabetic cardiomyopathy induced by high-fat diet plus streptozotocin (STZ) injection in CD38 knockout (CD38-KO) mice. We observed that CD38 expression was up-regulated, whereas the expression of Sirt3 was down-regulated in the hearts of diabetic mice. CD38 deficiency significantly promoted glucose metabolism and improved cardiac functions, exemplified by increased left ventricular ejection fraction and fractional shortening. In addition, we observed that CD38 deficiency markedly decreased diabetes or high glucose and palmitic acid (HG + PA)-induced pyroptosis and apoptosis in CD38 knockout hearts or cardiomyocytes, respectively. Furthermore, we found that the expression levels of Sirt3, mainly located in mitochondria, and its target gene FOXO3a were increased in CD38-deficient hearts and cardiomyocytes with CD38 knockdown under diabetic induction conditions. In conclusion, we demonstrated that CD38 deficiency protected mice from diabetes-induced diabetic cardiomyopathy by reducing pyroptosis and apoptosis via activating NAD/Sirt3/FOXO3a signaling pathways.
Topics: Animals; Mice; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Mammals; Myocytes, Cardiac; NAD; Oxidative Stress; Pyroptosis; Sirtuin 3; Stroke Volume; Ventricular Function, Left
PubMed: 37958991
DOI: 10.3390/ijms242116008 -
Life Sciences Nov 2023Diabetic Mellitus has been characterized as the most prevalent disease throughout the globe associated with the serious morbidity and mortality of vital organs.... (Review)
Review
Diabetic Mellitus has been characterized as the most prevalent disease throughout the globe associated with the serious morbidity and mortality of vital organs. Cardiomyopathy is the major leading complication of diabetes and within this, myocardial dysfunction or failure is the leading cause of the emergency hospital admission. The review is aimed to comprehend the perspectives associated with diabetes-induced cardiovascular complications. The data was collected from several electronic databases such as Google Scholar, Science Direct, ACS publication, PubMed, Springer, etc. using the keywords such as diabetes and its associated complication, the prevalence of diabetes, the anatomical and physiological mechanism of diabetes-induced cardiomyopathy, the molecular mechanism of diabetes-induced cardiomyopathy, oxidative stress, and inflammatory stress, etc. The collected scientific data was screened by different experts based on the inclusion and exclusion criteria of the study. This review findings revealed that diabetes is associated with inefficient substrate utilization, inability to increase glucose metabolism and advanced glycation end products within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity, and initially subclinical cardiac dysfunction and finally in overt heart failure. Furthermore, several factors such as hypertension, overexpression of renin angiotensin system, hypertrophic obesity, etc. have been seen as majorly associated with cardiomyopathy. The molecular examination showed biochemical disability and generation of the varieties of free radicals and inflammatory cytokines and becomes are the substantial causes of cardiomyopathy. This review provides a better understanding of the involved pathophysiology and offers an open platform for discussing and targeting therapy in alleviating diabetes-induced early heart failure or cardiomyopathy.
Topics: Humans; Diabetic Cardiomyopathies; Heart Failure; Oxidative Stress; Diabetes Mellitus
PubMed: 37714373
DOI: 10.1016/j.lfs.2023.122087 -
International Immunopharmacology Oct 2023Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However,... (Review)
Review
Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However, treatment options for DCM remain limited. For decades, a substantial body of evidence has suggested that the inflammatory response plays a pivotal role in the development and progression of DCM. Notably, DCM is closely associated with alterations in inflammatory cells, exerting direct effects on major resident cells such as cardiomyocytes, vascular endothelial cells, and fibroblasts. These cellular changes subsequently contribute to the development of DCM. This article comprehensively analyzes cellular, animal, and human studies to summarize the latest insights into the impact of inflammation on DCM. Furthermore, the potential therapeutic effects of current anti-inflammatory drugs in the management of DCM are also taken into consideration. The ultimate goal of this work is to consolidate the existing literature on the inflammatory processes underlying DCM, providing clinicians with the necessary knowledge and tools to adopt a more efficient and evidence-based approach to managing this condition.
Topics: Animals; Humans; Diabetic Cardiomyopathies; Endothelial Cells; Inflammation; Myocytes, Cardiac; Anti-Inflammatory Agents; Diabetes Mellitus
PubMed: 37586299
DOI: 10.1016/j.intimp.2023.110747 -
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 -
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 -
Pharmacology Research & Perspectives Apr 2024Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, in the absence of coronary artery disease,... (Review)
Review
Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, in the absence of coronary artery disease, valve disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. It is considered a significant and consequential complication of diabetes in the field of cardiovascular medicine. The primary pathological manifestations include myocardial hypertrophy, myocardial fibrosis, and impaired ventricular function, which can lead to widespread myocardial necrosis. Ultimately, this can progress to the development of heart failure, arrhythmias, and cardiogenic shock, with severe cases even resulting in sudden cardiac death. Despite several decades of both fundamental and clinical research conducted globally, there are currently no specific targeted therapies available for DCM in clinical practice, and the incidence and mortality rates of heart failure remain persistently high. Thus, this article provides an overview of the current treatment modalities and novel techniques pertaining to DCM, aiming to offer valuable insights and support to researchers dedicated to investigating this complex condition.
Topics: Humans; Diabetic Cardiomyopathies; Heart Failure; Coronary Artery Disease; Myocardial Infarction; Cardiovascular Agents; Diabetes Mellitus
PubMed: 38407563
DOI: 10.1002/prp2.1177 -
Acta Pharmacologica Sinica Jun 2024Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the...
Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 μM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD precursor Niacin (50 μM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM. Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD-SIRT3 axis.
Topics: Animals; Male; Mice; Rats; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diet, High-Fat; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; NAD; Oxidative Stress; Palmitic Acid; Poly (ADP-Ribose) Polymerase-1; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 3; Streptozocin
PubMed: 38459256
DOI: 10.1038/s41401-024-01247-2 -
Experimental Physiology Feb 2024Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial... (Review)
Review
Diabetic cardiomyopathy (DCM) is a significant cause of heart failure in patients with diabetes, and its pathogenesis is closely related to myocardial mitochondrial injury and functional disability. Studies have shown that the development of diabetic cardiomyopathy is related to disorders in mitochondrial metabolic substrates, changes in mitochondrial dynamics, an imbalance in mitochondrial Ca regulation, defects in the regulation of microRNAs, and mitochondrial oxidative stress. Physical activity may play a role in resistance to the development of diabetic cardiomyopathy by improving myocardial mitochondrial biogenesis, the level of autophagy and dynamic changes in fusion and division; enhancing the ability to cope with oxidative stress; and optimising the metabolic substrates of the myocardium. This paper puts forward a new idea for further understanding the specific mitochondrial mechanism of the occurrence and development of diabetic cardiomyopathy and clarifying the role of exercise-mediated myocardial mitochondrial changes in the prevention and treatment of diabetic cardiomyopathy. This is expected to provide a new theoretical basis for exercise to reduce diabetic cardiomyopathy symptoms.
Topics: Humans; Diabetic Cardiomyopathies; Mitochondria, Heart; Myocardium; Exercise; Oxidative Stress; Diabetes Mellitus
PubMed: 37845840
DOI: 10.1113/EP091309 -
Tissue & Cell Dec 2023Diabetic cardiomyopathy (DCM) causes arrhythmia, heart failure, and sudden death. Empagliflozin, an SGLT-2 (Sodium glucose co-transporter) inhibitor, is an anti-diabetic...
UNLABELLED
Diabetic cardiomyopathy (DCM) causes arrhythmia, heart failure, and sudden death. Empagliflozin, an SGLT-2 (Sodium glucose co-transporter) inhibitor, is an anti-diabetic medication that decreases blood glucose levels by stimulating urinary glucose excretion. Several aquaporins (AQPs) including AQP-1-3 and - 4 and their involvement in the pathogenesis in different cardiac diseases were detected. In the current study the effect of Empagliflozin on diabetic cardiomyopathy and the possible involvement of cardiac AQPs were investigated.
METHODS
56 adult male Sprague-Dawley rats were divided into 4 groups: Control, DCM: type 2 diabetic rats, low EMPA+DCM received empagliflozin (10 mg/kg/day) and high EMPA+DCM received empagliflozin (30 mg/kg/day) for 6 weeks.
RESULTS
Administration of both EMPA doses, especially in high dose group, led to significant improvement in ECG parameters. Also, a significant improvement in biochemical and cardiac oxidative stress markers (significant decrease in serum CK-MB, and malondialdehyde while increasing catalase) with decreased fibrosis and edema in histopathological examination and a significant attenuation in apoptosis (caspase-3) and edema (AQP-1& -4).
CONCLUSION
Both doses of Empagliflozin have a cardioprotective effect and reduced myocardial tissue edema with high dose having a greater effect. This might be due to attenuation of oxidative stress, fibrosis and edema mediated through AQP-1, - 3& - 4 expression.
Topics: Animals; Male; Rats; Aquaporins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Edema; Fibrosis; Glucose; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37660414
DOI: 10.1016/j.tice.2023.102200