-
Redox Biology Jul 2024The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic...
RATIONALE
The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, the precise roles of Sirt5 in cardiac lipotoxicity and DbCM remain unknown.
OBJECTIVE
This study aims to elucidate the role and underlying mechanism of Sirt5 in the context of cardiac lipotoxicity and DbCM.
METHODS AND RESULTS
The expression of myocardial Sirt5 was found to be modestly elevated in diabetic heart failure patients and mice. Cardiac dysfunction, hypertrophy and lipotoxicity were exacerbated by ablation of Sirt5 but improved by forced expression of Sirt5 in diabetic mice. Notably, Sirt5 deficiency impaired FAO without affecting the capacity of FA uptake in the diabetic heart, leading to accumulation of FA intermediate metabolites, which mainly included medium- and long-chain fatty acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), a crucial enzyme involved in the reconversion of fatty acyl-carnitines to fatty acyl-CoA and facilitating FAO, as the functional succinylated substrate mediator of Sirt5. Succinylation of Lys424 in CPT2 was significantly increased by Sirt5 deficiency, leading to the inactivation of its enzymatic activity and the subsequent accumulation of fatty acyl-carnitines. CPT2 K424R mutation, which mitigated succinylation modification, counteracted the reduction of enzymatic activity in CPT2 mediated by Sirt5 deficiency, thereby attenuating Sirt5 knockout-induced FAO impairment and lipid deposition.
CONCLUSIONS
Sirt5 deficiency impairs FAO, leading to cardiac lipotoxicity in the diabetic heart through the succinylation of Lys424 in CPT2. This underscores the potential roles of Sirt5 and CPT2 as therapeutic targets for addressing DbCM.
Topics: Animals; Diabetic Cardiomyopathies; Carnitine O-Palmitoyltransferase; Sirtuins; Mice; Fatty Acids; Myocytes, Cardiac; Humans; Lipid Metabolism; Male; Oxidation-Reduction; Diabetes Mellitus, Experimental
PubMed: 38718533
DOI: 10.1016/j.redox.2024.103184 -
The American Journal of Chinese Medicine 2024A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy...
A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet . Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group and . Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.
Topics: Animals; Autophagy; Apoptosis; TOR Serine-Threonine Kinases; Quercetin; Signal Transduction; Diabetes Mellitus, Experimental; Male; AMP-Activated Protein Kinases; Rats, Sprague-Dawley; Rats; Disease Models, Animal; Myocardium; Streptozocin; Diabetic Cardiomyopathies; Phytotherapy; Beclin-1; Oxidative Stress; Diabetes Mellitus, Type 2
PubMed: 38716618
DOI: 10.1142/S0192415X24500344 -
Cardiovascular Diabetology May 2024Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure....
BACKGROUND
Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism.
METHODS AND RESULTS
Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα).
CONCLUSION
These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.
Topics: Animals; Pyroptosis; Diabetic Cardiomyopathies; Myocytes, Cardiac; Mice, Inbred C57BL; Diabetes Mellitus, Experimental; Cell Line; Inflammasomes; Male; Fibrosis; Signal Transduction; Growth Differentiation Factors; Rats; Blood Glucose; Mice; Glucose; Bone Morphogenetic Proteins; PPAR alpha
PubMed: 38715043
DOI: 10.1186/s12933-024-02258-3 -
Journal of Pharmacy & Pharmaceutical... 2024Unhealthy sources of fats, ultra-processed foods with added sugars, and a sedentary lifestyle make humans more susceptible to developing overweight and obesity. While... (Review)
Review
Unhealthy sources of fats, ultra-processed foods with added sugars, and a sedentary lifestyle make humans more susceptible to developing overweight and obesity. While lipids constitute an integral component of the organism, excessive and abnormal lipid accumulation that exceeds the storage capacity of lipid droplets disrupts the intracellular composition of fatty acids and results in the release of deleterious lipid species, thereby giving rise to a pathological state termed lipotoxicity. This condition induces endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory responses, and cell death. Recent advances in omics technologies and analytical methodologies and clinical research have provided novel insights into the mechanisms of lipotoxicity, including gut dysbiosis, epigenetic and epitranscriptomic modifications, dysfunction of lipid droplets, post-translational modifications, and altered membrane lipid composition. In this review, we discuss the recent knowledge on the mechanisms underlying the development of lipotoxicity and lipotoxic cardiometabolic disease in obesity, with a particular focus on lipotoxic and diabetic cardiomyopathy.
Topics: Humans; Obesity; Diabetic Cardiomyopathies; Animals; Lipid Metabolism
PubMed: 38706718
DOI: 10.3389/jpps.2024.12568 -
Scientific Reports May 2024Diabetic individuals with diabetic cardiomyopathy (DbCM) present with abnormal myocardial structure and function. DbCM cannot be accurately diagnosed due to the lack of...
Diabetic individuals with diabetic cardiomyopathy (DbCM) present with abnormal myocardial structure and function. DbCM cannot be accurately diagnosed due to the lack of suitable diagnostic biomarkers. In this study, 171 eligible participants were divided into a healthy control (HC), type 2 diabetes mellitus (T2DM) patients without DbCM (T2DM), or DbCM group. Serum fibrinogen-like protein 1 (FGL-1) and other biochemical parameters were determined for all participants. Serum FGL-1 levels were significantly higher in patients with DbCM compared with those in the T2DM group and HCs. Serum FGL-1 levels were negatively correlated with left ventricular fractional shortening and left ventricular ejection fraction (LVEF) and positively correlated with left ventricular mass index in patients with DbCM after adjusting for age, sex and body mass index. Interaction of serum FGL-1 and triglyceride levels on LVEF was noted in patients with DbCM. A composite marker including serum FGL-1 and triglycerides could differentiate patients with DbCM from those with T2DM and HCs with an area under the curve of 0.773 and 0.789, respectively. Composite marker levels were negatively correlated with N-terminal B-type natriuretic peptide levels in patients with DbCM. Circulating FGL-1 may therefore be a valuable index reflecting cardiac functions in DbCM and to diagnose DbCM.
Topics: Humans; Male; Female; Fibrinogen; Diabetic Cardiomyopathies; Biomarkers; Middle Aged; Diabetes Mellitus, Type 2; Aged; Ventricular Function, Left; Case-Control Studies; Stroke Volume; Triglycerides
PubMed: 38705920
DOI: 10.1038/s41598-024-57580-3 -
Nature Metabolism Jun 2024Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular...
Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.
Topics: Animals; Receptors, G-Protein-Coupled; Diabetic Cardiomyopathies; Mice; Male; Female; Fatty Acids; Humans; Mice, Knockout; Bile Acids and Salts; Diet, High-Fat; CD36 Antigens; Myocardium; Lipid Metabolism; Myocytes, Cardiac; Diabetes Mellitus, Experimental
PubMed: 38698281
DOI: 10.1038/s42255-024-01036-5 -
Nature Metabolism Jun 2024
Topics: Bile Acids and Salts; Diabetic Cardiomyopathies; Humans; Animals
PubMed: 38698280
DOI: 10.1038/s42255-024-01032-9 -
European Journal of Pharmacology Jul 2024Diabetic cardiomyopathy is a prevalent cardiovascular complication of diabetes mellitus. This study aimed to investigate the effects of ginsenoside Rb1 (GRb1) on the...
PURPOSE
Diabetic cardiomyopathy is a prevalent cardiovascular complication of diabetes mellitus. This study aimed to investigate the effects of ginsenoside Rb1 (GRb1) on the diabetic myocardium.
METHODS
Leptin receptor-deficient db/db mice and palmitic acid (PA)-treated cardiomyocyte models were utilized. Cardiac systolic and diastolic function, mitochondrial morphology, and respiratory chain function were determined. The expression of mitochondrial dynamics proteins was measured. Mitofusin 2 (Mfn2) overexpression and inhibition were achieved by lentiviral infection and small interfering RNA (siRNA) transfection.
RESULTS
In comparison to non-diabetic mice, db/db mice exhibited significant increases in body weight, blood glucose, blood lipids, and cardiac free fatty acid levels. This was accompanied by myocardial hypertrophy and left ventricular diastolic dysfunction, which were significantly ameliorated by GRb1 intervention. Stimulation with PA increased oxidative stress and apoptosis, and decreased viability in H9c2 cardiomyocytes. PA also reduced sarcomere contractility and relaxation in adult mice ventricular myocytes. PA-induced cellular and mitochondrial damage were reversed with GRb1 treatment. The cardiac tissue of db/db mice and PA-treated cardiomyocytes exhibited a decrease in Mfn2 expression, which was markedly improved by GRb1. Mfn2 overexpression reversed PA-induced mitochondrial fragmentation and functional damage in cardiomyocytes, while inhibition of Mfn2 expression by siRNA transfection blocked the protective effects of GRb1.
CONCLUSION
GRb1 alleviated myocardial lipid accumulation and mitochondrial injury, and attenuated ventricular diastolic dysfunction in diabetic mice. The regulation of Mfn2 was involved in the protective effects of GRb1 against lipotoxic myocardial injury.
Topics: Animals; Ginsenosides; Myocytes, Cardiac; Diabetic Cardiomyopathies; Mice; GTP Phosphohydrolases; Male; Palmitic Acid; Apoptosis; Oxidative Stress; Diabetes Mellitus, Experimental; Rats; Receptors, Leptin; Cell Line; Mice, Inbred C57BL; Myocardium
PubMed: 38677536
DOI: 10.1016/j.ejphar.2024.176609 -
Journal of Translational Medicine Apr 2024The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in...
BACKGROUND
The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated.
METHODS
Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments.
RESULTS
Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10.
CONCLUSIONS
The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.
Topics: Animals; Male; Mice; Apoptosis; Caveolin 3; Diabetic Cardiomyopathies; Electron Transport Complex I; Mice, Inbred C57BL; Mitochondria; Mitochondria, Heart; Myocytes, Cardiac
PubMed: 38671439
DOI: 10.1186/s12967-024-05223-6 -
Cardiovascular Diabetology Apr 2024Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and...
BACKGROUND
Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM's unique cell states and molecular landscape for targeted therapeutic interventions.
METHODS
Single-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings.
RESULTS
This study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation.
CONCLUSION
Our integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.
Topics: Diabetic Cardiomyopathies; Animals; Single-Cell Analysis; Transcriptome; Gene Expression Profiling; Chromatin; Mice, Inbred C57BL; Gene Regulatory Networks; Chromatin Assembly and Disassembly; Disease Models, Animal; Male; RNA-Seq; Gene Expression Regulation; Myocytes, Cardiac; Fibroblasts; Fibrosis; Mice; Endothelial Cells
PubMed: 38664790
DOI: 10.1186/s12933-024-02233-y