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C1q-TNF-Related Protein-9 protects from diabetic cardiomyopathy by alleviating cardiac insulin resistance and inflammation

ABSTRACT: Diabetic cardiomyopathy is a major health problem world wide. CTRP9 is a secreted glycoprotein, which is mainly expressed in endothelial cells of the heart. In this study, we investigated the impact of CTRP9 on diabetic cardiomyopathy induced by high fat diet feeding. While the lack of CTRP9 in knock-out mice aggravated the disease, AAV9 mediated cardiac CTRP9 overexpression ameliorated diastolic cardiac dysfunction under these conditions. Mechanistically, we found that CTRP9 is required for insulin dependent cardiac glucose uptake and metabolism and that it counteracts cardiac inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE219101 | GEO | 2023/02/15

REPOSITORIES: GEO

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Project description:VEGF family members are important regulators of vascular functions. Promoting VEGFA signalling in aged mice has been shown to delay various aging phenotypes and extend the survival of aged mice. Although there is profound knowledge on functions of VEGFA, VEGFB has not been investigated in the context of cardiac aging. Our RNA data of aged mouse hearts revealed significant downregulation of Vegfb in the heart, specifically in endothelial cells and cardiomyocytes, while VEGFB expression was reduced in endothelial cells, fibroblasts and cardiomyocytes in aged human hearts. By contrast, VEGFB expression was exclusively reduced in cardiomyocytes of patients with cardiac hypertrophy. Hence, we investigated whether Vegfb gene therapy can revert age-dependent cardiac pathologies. We overexpressed Vegfb186, the soluble VEGFB isoform, via AAV9 vector transduction into 18-month-old C57Bl/6J male mice. AAV9-Vegfb treatment prevented progression age-related diastolic dysfunction and decreased cardiac fibrosis. We further found a rescue of aging-related left ventricular denervation in the hearts of AVV9-Vegfb treated old mice which was associated with an increase in heart rate variability. However, heart to body weight ratio and cardiomyocyte hypertrophy were increased in the AAV9-Vegfb treated mouse hearts, without alteration of cardiac systolic or diastolic function. Histological and transcriptomic analyses revealed that VEGFB186 induces compensatory cardiac hypertrophy which was accompanied by a rescued length-width-ratio, reduced fibrosis and the absence of cardiac inflammation. Cardiac single-nuclei RNA sequencing further suggested that AAV9-Vegfb treatment affects cardiac hypertrophy putatively via STAT3 which was validated in vitro. In conclusion, our data reveals that Vegfb overexpression partially reverses pathological alterations in the aging heart. Despite the overall improvement of the age-related cardiac phenotype, the AAV9-Vegfb-mediated induced cardiac hypertrophy which might reflect protective hypertrophy.

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C1q-TNF-Related Protein-9 protects from diabetic cardiomyopathy by alleviating cardiac insulin resistance and inflammation

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