Dataset Information

Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress.

ABSTRACT: Diabetic cardiomyopathy (DCM) is a kind of heart disease that affects diabetic patients and is one of the primary causes of death. We previously demonstrated that deletion of the general control nonderepressible 2 (GCN2) kinase ameliorates cardiac dysfunction in diabetic mice. The aim of this study was to investigate the protective effect of GCN2iB, a GCN2 inhibitor, in type 2 diabetic (T2D) mice induced by a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments or deletion of the leptin receptor (db/db). GCN2iB (3 mg/kg/every other day) treatment for 6 weeks resulted in significant decreases in fasting blood glucose levels and body weight and increases in the left ventricular ejection fraction. GCN2iB treatment also attenuated myocardial fibrosis, lipid accumulation and oxidative stress in the hearts of T2D mice, which was associated with decreases in lipid metabolism-related genes and increases in antioxidative genes. Untargeted metabolomics and RNA sequencing analysis revealed that GCN2iB profoundly affected myocardial metabolomic profiles and gene expression profiles. In particular, GCN2iB increased myocardial phosphocreatine and taurine levels and upregulated genes involved in oxidative phosphorylation. In conclusion, the data provide evidence that GCN2iB effectively protects against cardiac dysfunction in T2D mice. Our findings suggest that GCN2iB might be a novel drug candidate for DCM therapy.

SUBMITTER: Yuan J

PROVIDER: S-EPMC9312289 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundMyocardial microvascular injury is the key event in early diabetic heart disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and trigger of myocardial microvascular disease. Mitochondrial calcium homeostasis plays an important role in maintaining the normal function, survival and death of endothelial cells. Considering that mitochondrial calcium uptake 1 (MICU1) is a key molecule in mitochondrial calcium regulation, this study aimed to investigate the role of MICU1 in CMECs and explore its underlying mechanisms.MethodsTo examine the role of endothelial MICU1 in diabetic cardiomyopathy (DCM), we used endothelial-specific MICU1ecKO mice to establish a diabetic mouse model and evaluate the cardiac function. In addition, MICU1 overexpression was conducted by injecting adeno-associated virus 9 carrying MICU1 (AAV9-MICU1). Transcriptome sequencing technology was used to explore underlying molecular mechanisms.ResultsHere, we found that MICU1 expression is decreased in CMECs of diabetic mice. Moreover, we demonstrated that endothelial cell MICU1 knockout exacerbated the levels of cardiac hypertrophy and interstitial myocardial fibrosis and led to a further reduction in left ventricular function in diabetic mice. Notably, we found that AAV9-MICU1 specifically upregulated the expression of MICU1 in CMECs of diabetic mice, which inhibited nitrification stress, inflammatory reaction, and apoptosis of the CMECs, ameliorated myocardial hypertrophy and fibrosis, and promoted cardiac function. Further mechanistic analysis suggested that MICU1 deficiency result in excessive mitochondrial calcium uptake and homeostasis imbalance which caused nitrification stress-induced endothelial damage and inflammation that disrupted myocardial microvascular endothelial barrier function and ultimately promoted DCM progression.ConclusionsOur findings demonstrate that MICU1 expression was downregulated in the CMECs of diabetic mice. Overexpression of endothelial MICU1 reduced nitrification stress induced apoptosis and inflammation by inhibiting mitochondrial calcium uptake, which improved myocardial microvascular function and inhibited DCM progression. Our findings suggest that endothelial MICU1 is a molecular intervention target for the potential treatment of DCM.

Dataset Information

Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets