Pkcδ Activation is Involved in ROS-Mediated Mitochondrial Dysfunction and Apoptosis in Cardiomyocytes Exposed to Advanced Glycation End Products (Ages).

Abstract

Diabetic patients exhibit serum AGE accumulation, which is associated with reactive oxygen species (ROS) production and diabetic cardiomyopathy. ROS-induced PKCδ activation is linked to mitochondrial dysfunction in human cells. However, the role of PKCδ in cardiac and mitochondrial dysfunction caused by AGE in diabetes is still unclear. AGE-BSA-treated cardiac cells showed dose- and time-dependent cell apoptosis, ROS generation, and selective PKCδ activation, which were reversed by NAC and rotenone. Similar tendency was also observed in diabetic and obese animal hearts. Furthermore, enhanced apoptosis and reduced survival signaling by AGE-BSA or PKCδ-WT transfection were reversed by kinase-deficient (KD) of PKCδ transfection or PKCδ inhibitor, respectively, indicating that AGE-BSA-induced cardiomyocyte death is PKCδ-dependent. Increased levels of mitochondrial mass as well as mitochondrial fission by AGE-BSA or PKCδ activator were reduced by rottlerin, siPKCδ or KD transfection, indicating that the AGE-BSA-induced mitochondrial damage is PKCδ-dependent. Using super-resolution microscopy, we confirmed that PKCδ colocalized with mitochondria. Interestingly, the mitochondrial functional analysis by Seahorse XF-24 flux analyzer showed similar results. Our findings indicated that cardiac PKCδ activation mediates AGE-BSA-induced cardiomyocyte apoptosis via ROS production and may play a key role in the development of cardiac mitochondrial dysfunction in rats with diabetes and obesity.

• Authors: Yao-Chih Yang, Cheng-Yen Tsai, Chien-Lin Chen, Chia-Hua Kuo, Chien-Wen Hou, Shi-Yann Cheng, Ritu Aneja, Chih-Yang Huang, Wei-Wen Kuo
• Journal: Aging and disease (Aging Dis) Vol. 9 Issue 4 Pg. 647-663 (Aug 2018) ISSN: 2152-5250 [Print] United States
• PMID: 30090653 (Publication Type: Journal Article)