Hua Qu1, Ke Lin2, Hang Wang1, Huili Wei1, Baolan Ji1, Zengsong Yang1, Chuan Peng3, Xiaoqiu Xiao3, Huacong Deng1. 1. Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China. 2. Department of Neurology, Chongqing Emergency Medical Center (The Fourth People's Hospital of Chongqing), Chongqing, P. R. China. 3. Laboratory of Lipid and Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China.
Abstract
SCOPE: Diabetic cardiomyopathy is one of the most important cardiac complications associated with diabetes. However, the mechanisms underlying diabetic cardiomyopathy remain unclear. The PARP1, SIRT1, and mTOR pathways have been implicated in cardiac diseases, and they are also associated with diabetes. 1,25(OH)2 D3 was recently recognized as a potential PARP1inhibitor in a macrophage cell line. The aim of our study was to investigate whether 1,25(OH)2 D3 can improve diabetic cardiomyopathy through a vitamin D receptor (VDR)-dependent mechanism associated with the PARP1/SIRT1/mTOR pathway. METHODS AND RESULTS: 1,25(OH)2 D3 -treated diabetic rats displayed improved left ventricular wall thickness and end-diastolic/systolic diameter, end-diastolic/systolic volume, left ventricular ejection fraction, fractional shortening, atrial natriuretic peptide, and brain natriuretic peptide gene expression, and interstitial fibrosis compared with untreated diabetic rats, while silencing the VDR gene in DM rats blocked the above results. 1,25(OH)2 D3 treatment also decreased PARP1 and increased SIRT1 expression levels and repressed the phosphorylation of mTOR. Treating neonatal cardiomyocytes with 1,25(OH)2 D3 and a PARP1 inhibitor decreased PARP1 and increased SIRT1 protein expression. CONCLUSION: The present study demonstrates that 1,25(OH)2 D3 treatment has the potential to improve diabetic cardiomyopathy in rats and suggests that VD-VDR signaling induces this protective effect against diabetic cardiomyopathy might partly through the PARP1/SIRT1/mTOR pathway.
SCOPE: Diabetic cardiomyopathy is one of the most important cardiac complications associated with diabetes. However, the mechanisms underlying diabetic cardiomyopathy remain unclear. The PARP1, SIRT1, and mTOR pathways have been implicated in cardiac diseases, and they are also associated with diabetes. 1,25(OH)2 D3 was recently recognized as a potential PARP1inhibitor in a macrophage cell line. The aim of our study was to investigate whether 1,25(OH)2 D3 can improve diabetic cardiomyopathy through a vitamin D receptor (VDR)-dependent mechanism associated with the PARP1/SIRT1/mTOR pathway. METHODS AND RESULTS:1,25(OH)2 D3 -treated diabeticrats displayed improved left ventricular wall thickness and end-diastolic/systolic diameter, end-diastolic/systolic volume, left ventricular ejection fraction, fractional shortening, atrial natriuretic peptide, and brain natriuretic peptide gene expression, and interstitial fibrosis compared with untreated diabeticrats, while silencing the VDR gene in DMrats blocked the above results. 1,25(OH)2 D3 treatment also decreased PARP1 and increased SIRT1 expression levels and repressed the phosphorylation of mTOR. Treating neonatal cardiomyocytes with 1,25(OH)2 D3 and a PARP1 inhibitor decreased PARP1 and increased SIRT1 protein expression. CONCLUSION: The present study demonstrates that 1,25(OH)2 D3 treatment has the potential to improve diabetic cardiomyopathy in rats and suggests that VD-VDR signaling induces this protective effect against diabetic cardiomyopathy might partly through the PARP1/SIRT1/mTOR pathway.
Authors: Charles Ginsberg; Leila R Zelnick; Geoffrey A Block; Glenn M Chertow; Michel Chonchol; Andrew Hoofnagle; Bryan Kestenbaum; Ian H de Boer Journal: Nephrol Dial Transplant Date: 2020-04-01 Impact factor: 5.992