SFRP2 Improves Mitochondrial Dynamics and Mitochondrial Biogenesis, Oxidative Stress, and Apoptosis in Diabetic Cardiomyopathy.

Tianyi Ma,Guolin Huang,Yuli Huang,Yue Cao,Yunzhao Hu,Haoxiao Zheng,Jingjing Liang,Xiaohui Huang,Xinyue Liu,Weiwen Li,Yue Liu

doi:10.1155/2021/9265016

Abstract

Background The mitochondrial dynamics and mitochondrial biogenesis are essential for maintaining the bioenergy function of mitochondria in diabetic cardiomyopathy (DCM). Previous studies have revealed that secreted frizzled-related protein 2 (SFRP2) is beneficial against apoptosis and oxidative stress. However, no research has confirmed whether SFRP2 regulates oxidative stress and apoptosis through mitochondrial function in DCM. Methods Exposure of H9C2 cardiomyocytes in high glucose (HG) 25 mM and palmitic acid (PAL) 0.2 mM was used to simulate DCM in vitro. H9C2 cells with SFRP2 overexpression or SFRP2 knockdown were constructed and cultured under glucolipotoxicity or normal glucose conditions. An SD rat model of type 2 diabetes mellitus (T2DM) was generated using a high-fat diet combined with a low-dose STZ injection. Overexpression of SFRP2 in the rat model was generated by using an adeno-associated virus approach. CCK-8, TUNEL assay, and DHE staining were used to detect cell viability, and MitoTracker Red CMXRos was used to detect changes in mitochondrial membrane potential. We used qRT-PCR and western blot to further explore the mechanisms of SFRP2 regulating mitochondrial dynamics through the AMPK/PGC1-α pathway to improve diabetic cardiomyocyte injury. Results Our results indicated that SFRP2 was significantly downregulated in H9C2 cells and cardiac tissues in T2DM conditions, accompanied by decreased expression of mitochondrial dysfunction. The mitochondrial membrane potential was reduced, and the cells were led to oxidative stress injury and apoptosis. Furthermore, the overexpression of SFRP2 could reverse apoptosis and promote mitochondrial function in T2DM conditions in vitro and in vivo. We also found that silencing endogenous SFRP2 could further promote glucolipotoxicity-induced mitochondrial dysfunction and apoptosis in cardiomyocytes, accompanied by downregulation of p-AMPK. Conclusion SFRP2 exerted cardioprotective effects by salvaging mitochondrial function in an AMPK-PGC1-α-dependent manner, which modulates mitochondrial dynamics and mitochondrial biogenesis, reducing oxidative stress and apoptosis. SFRP2 may be a promising therapeutic biomarker in DCM.

Highlights

Diabetes and its complications have become a public health issue of great concern
The aims of the present study were (1) to clarify the molecular signaling of glucolipotoxicity that leads to impaired mitochondrial dynamics and mitochondrial biogenesis of cardiomyocytes and (2) to verify whether secreted frizzled-related protein 2 (SFRP2) can reduce the oxidation stress, apoptosis, and mitochondrial dynamics and mitochondrial biogenesis of cardiomyocytes caused by glucolipotoxicity and illustrate the underlying mechanisms
These results demonstrated that glucolipotoxicity increased oxidative stress and promoted apoptosis in H9C2 cells

Summary

Introduction

Diabetes and its complications have become a public health issue of great concern. The leading cause of death in diabetic patients is cardiovascular disease [1]. No research has confirmed whether SFRP2 regulates oxidative stress and apoptosis through mitochondrial function in DCM. Our results indicated that SFRP2 was significantly downregulated in H9C2 cells and cardiac tissues in T2DM conditions, accompanied by decreased expression of mitochondrial dysfunction. The mitochondrial membrane potential was reduced, and the cells were led to oxidative stress injury and apoptosis. The overexpression of SFRP2 could reverse apoptosis and promote mitochondrial function in T2DM conditions in vitro and in vivo. We found that silencing endogenous SFRP2 could further promote glucolipotoxicity-induced mitochondrial dysfunction and apoptosis in cardiomyocytes, accompanied by downregulation of p-AMPK. SFRP2 exerted cardioprotective effects by salvaging mitochondrial function in an AMPK-PGC1-α-dependent manner, which modulates mitochondrial dynamics and mitochondrial biogenesis, reducing oxidative stress and apoptosis.

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