期刊
AGING AND DISEASE
卷 9, 期 4, 页码 647-663出版社
INT SOC AGING & DISEASE
DOI: 10.14336/AD.2017.0924
关键词
advanced glycation end products (AGEs); apoptosis; diabetes mellitus (DM); mitochondrial; protein kinase C (PKC)delta; reactive oxygen species (ROS)
资金
- Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence [MOHW106-TDU-B-212-113004]
- China Medical University [CMU105-S-32]
- Ministry of Science and Technology [MOST 106-2320-B-039-038]
Diabetic patients exhibit serum AGE accumulation, which is associated with reactive oxygen species (ROS) production and diabetic cardiomyopathy. ROS-induced PKC delta activation is linked to mitochondrial dysfunction in human cells. However, the role of PKC delta 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 PKC delta 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 PKC delta-WT transfection were reversed by kinase-deficient (KD) of PKC delta transfection or PKC delta inhibitor, respectively, indicating that AGE-BSA-induced cardiomyocyte death is PKC delta-dependent. Increased levels of mitochondrial mass as well as mitochondrial fission by AGE-BSA or PKC delta activator were reduced by rottlerin, siPKC delta or KD transfection, indicating that the AGE-BSA-induced mitochondrial damage is PKC delta-dependent. Using super-resolution microscopy, we confirmed that PKC delta colocalized with mitochondria. Interestingly, the mitochondrial functional analysis by Seahorse XF-24 flux analyzer showed similar results. Our findings indicated that cardiac PKC delta 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.
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