P2X7 Receptor Deficiency Ameliorates STZ-induced Cardiac Damage and Remodeling Through PKCβ and ERK.

Shanjun Huang,Weijian Huang,Weiqi Wang,Ya Lin,Yihan Zhao,Ting Wang,Li Li,Yonghua Wang,Zhouqing Huang

doi:10.3389/fcell.2021.692028

Abstract

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus which result in cardiac remodeling and subsequent heart failure. However, the role of P2X7 receptor (P2X7R) in DCM has yet to be elucidated. The principal objective of this study was to investigate whether P2X7R participates in the pathogenesis of DCM. In this study, the C57BL/6 diabetic mouse model was treated with a P2X7R inhibitor (A438079). Cardiac dysfunction and remodeling were attenuated by the intraperitoneal injection of A438079 or P2X7R deficiency. In vitro, A438079 reduced high glucose (HG) induced cell damage in H9c2 cells and primary rat cardiomyocytes. Furthermore, HG/streptozotocin (STZ)-induced P2X7R activation mediated downstream protein kinase C-β (PKCβ) and extracellular regulated protein kinases (ERK) activation. This study provided evidence that P2X7R plays an important role in the pathogenesis of STZ-induced diabetic cardiac damage and remodeling through the PKCβ/ERK axis and suggested that P2X7R might be a potential target in the treatment of diabetic cardiomyopathy.

Highlights

Many patients are diagnosed with diabetes worldwide, and the complications caused by diabetes are diverse, such as diabetic nephropathy, diabetic retinopathy, and diabetic heart diseases
This study provided evidence that P2X7 receptor (P2X7R) plays an important role in the pathogenesis of STZ-induced diabetic cardiac damage and remodeling through the protein kinase C-β (PKCβ)/extracellular regulated protein kinases (ERK) axis and suggested that P2X7R might be a potential target in the treatment of diabetic cardiomyopathy
We systematically revealed the novel role of the P2X7R in diabetic cardiomyopathy (DCM)

Summary

Introduction

Many patients are diagnosed with diabetes worldwide, and the complications caused by diabetes are diverse, such as diabetic nephropathy, diabetic retinopathy, and diabetic heart diseases Among these complications, diabetic cardiomyopathy (DCM) is a serious complication that results in a poor prognosis for patients with diabetes (Zhao et al, 2012; Forbes and Cooper, 2013; Ofstad, 2016; Ogurtsova et al, 2017). DCM is characterized by structural and functional disorders, including ventricular dysfunction, interstitial fibrosis, cardiomyocyte hypertrophy, myocardial apoptosis, and metabolic deregulation (Wang et al, 2006). These pathophysiological changes eventually lead to cardiac remodeling and decreased cardiac output, preventing the heart from adequately pumping blood. An effective drug or target to treat DCM must be identified

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