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

Abstract

Background: Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus which result in cardiac remodeling and subsequent heart failure. However, the role of the 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. Methods: The C57BL/6 mice were induced by STZ and treated with a P2X7R inhibitor (A438079). Cardiac dysfunction and remodeling were detected by two-dimensional B-ultrasound, Western blot (WB), quantitative PCR (qPCR), immunofluorescence, immunohistochemistry and so on. P2X7R knockout (P2X7R-/-) mouse models were used to assess the role of the P2X7R in diabetic cardiomyopathy. Cell hypertrophy, apoptosis, and fibrosis were assessed in H9c2 cells and primary rat cardiomyocytes treated with A438079. Protein kinase C-β (PKC-β) and extracellular regulated protein kinases (ERK) activation was examined by immunoblotting. Findings: Cardiac dysfunction and remodeling were attenuated by the intraperitoneal injection of A438079 or P2X7R deficiency. In vitro, A438079 reduced high-glucose induced cell damage in H9c2 cells and primary rat cardiomyocytes. Furthermore, HG/STZ-induced P2X7R activation mediated downstream protein kinase C-β (PKC-β) and extracellular regulated protein kinases (ERK)activation. Funding: This study was supported by the National Natural Science Foundation of China (grant numbers 81670227 and 82070446), the Wenzhou Science and Technology Bureau (grant no. Y2020242 and Y20180099), and the Key Research and Development Program of Zhejiang (grant no. 2019C03012). Declaration of Interest: The authors have declared no conflicts of interest. Ethical Approval: Animals: All operations were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Animal care and experimental protocols were approved by the Committee on Animal Care of Wenzhou Medical University.