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Aging Dis. 2018 Aug 1;9(4):647-663. doi: 10.14336/AD.2017.0924. eCollection 2018 Aug.

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

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1Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taiwan.
2Department of Pediatrics, China Medical University Beigang Hospital, Taiwan.
3School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taiwan.
4Department of Life Sciences, National Chung Hsing University, Taiwan.
5Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan.
6Graduate Institute of Physical Therapy and Rehabilitation Science, China Medical University, Taiwan.
7Department of Medical Education and Research and Department of Obstetrics and Gynecology, China Medical University Beigang Hospital, Taiwan.
8Department of Obstetrics and Gynecology, China Medical University An Nan Hospital, Taiwan.
9Obstetrics and Gynecology, School of Medicine, China Medical University, Taichung, Taiwan.
10Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
11Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Graduate Institute of Chinese Medical Science, School of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
Contributed equally


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.


advanced glycation end products (AGEs); apoptosis; diabetes mellitus (DM); mitochondrial; protein kinase C (PKC)δ; reactive oxygen species (ROS)

Conflict of interest statement

Competing Interests The authors declare that they have no competing interests.

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