SIRT3 is a downstream target of PPAR-α implicated in high glucose-induced cardiomyocyte injury in AC16 cells

Zong,Xiaojuan; Cheng,Kuan; Yin,Guizhi; Wu,Zhaodi; Su,Qian; Yu,Dong; Liao,Pengfei; Hu,Wei; Chen,Yueguang

doi:10.3892/etm.2020.8860

SIRT3 is a downstream target of PPAR-α implicated in high glucose-induced cardiomyocyte injury in AC16 cells

Authors:
- Xiaojuan Zong
- Kuan Cheng
- Guizhi Yin
- Zhaodi Wu
- Qian Su
- Dong Yu
- Pengfei Liao
- Wei Hu
- Yueguang Chen
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Affiliations: Department of Cardiology, Central Hospital of Minhang District, Shanghai 201100, P.R. China, Department of Cardiology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, P.R. China
Published online on: June 10, 2020 https://doi.org/10.3892/etm.2020.8860
Pages: 1261-1268
Copyright: © Zong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diabetic cardiomyopathy (DCM) is a worldwide public health concern that continues to display rapid growth trends. This study investigated the function of sirtuin 3 (SIRT3), a primary mitochondrial deacetylase with important roles in antioxidant defense and oxidative metabolism, during high glucose‑induced cardiomyocyte (AC16 cell) injury. Peroxisome proliferator‑activated receptor‑α (PPAR‑α) is directly related to the occurrence of DCM. Hence, we further examined the relationship between SIRT3 and PPAR‑α. AC16 cells were treated with various concentrations of glucose. Relative mRNA expression and protein levels were detected by RT‑qPCR and western blot analysis, respectively. Cell proliferation and apoptosis were assessed using CCK8 and Annexin V‑FITC apoptosis detection kits, respectively. DCFH‑DA assay was used to measure reactive oxygen species (ROS) accumulation. The results indicated that high glucose treatment reduced the expression of mRNA and protein of SIRT3 and PPAR‑α in AC16 cells. Moreover, high glucose inhibited cell proliferation, as well as induced apoptosis, intracellular hydrogen peroxide production, and JNK1/2 phosphorylation. These effects were antagonized by SIRT3 overexpression or treatment with the PPAR‑α agonist, Wy14643. Conversely, inhibition of SIRT3 via 3‑TYP led to similar phenomena as those induced by high glucose treatment in AC16 cells, which were blocked by Wy14643. Lastly, chromatin immunoprecipitation (ChIP) and luciferase assays demonstrated SIRT3 as a direct target of PPAR‑α. Taken together, the results provide evidence for an important role of SIRT3 in high glucose‑induced cardiomyocyte injury and regulation of JNK1/2 signaling. Further, SIRT3 is a direct downstream target of PPAR‑α.

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