title: Activated protein C prevents methylglyoxal-induced endoplasmic reticulum stress and cardiomyocyte apoptosis via regulation of the AMP-activated protein kinase signaling pathway.
abstract: Previous epidemiological studies have shown that methylglyoxal (MGO) levels are highly regulated in diabetic cardiovascular diseases. We have also previously reported that MGO mediates ER stress and apoptosis in cardiomyocytes. Furthermore, activated protein C (APC) has recently been shown to play a protective role against ER stress, as well as a cardioprotective role against ischemia and reperfusion injury by augmenting the AMP-activated protein kinase (AMPK) signaling pathway. Therefore, we hypothesized that APC protects against MGO-induced cardiomyocyte apoptosis through the inhibition of ER stress. Our results showed that APC inhibited MGO-induced cardiomyocyte apoptosis and ER stress-related gene expression. Additionally, APC inhibited MGO-induced Ca2+mobilization and the generation of reactive oxygen species. In contrast, inhibitors of AMPK signaling abolished the cytoprotective effects of APC. Collectively, these data depict a pivotal role for AMPK signaling in inhibiting ER stress responses via the activation of APC during MGO-induced cardiomyocyte apoptosis. Thus, APC may be a potential novel therapeutic target for the management of diabetic cardiovascular complications such as diabetic cardiomyopathy.
authors: Department of Pharmacology and Smart-aging Convergence Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, Republic of Korea.
authors: Dae-Hwan
authors: DH
authors: Nam
authors: Department of Pharmacology and Smart-aging Convergence Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, Republic of Korea.
authors: Jung-Hwa
authors: JH
authors: Han
authors: Department of Pharmacology and Smart-aging Convergence Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, Republic of Korea.
authors: Suji
authors: S
authors: Kim
authors: Division of AIDS, Center for Immunology and Pathology, Korea National Institute of Health, Cheongju, Chungcheongbuk-do, Republic of Korea.
authors: YoungHyun
authors: Y
authors: Shin
authors: Department of Microbiology, Ewha Womans University School of Medicine, 911-1 Mok-dong, Seoul, Republic of Korea.
authors: Jae Hyang
authors: JH
authors: Lim
authors: Department of Pharmacology and Smart-aging Convergence Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, Republic of Korea.
authors: Hyoung Chul
authors: HC
authors: Choi
authors: Department of Pharmacology and Smart-aging Convergence Research Center, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, Republic of Korea. Electronic address: changhoon_woo@yu.ac.kr.
authors: Chang-Hoon
authors: CH
authors: Woo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D011486:Protein C / Q000494:pharmacology*; D011765:Pyruvaldehyde / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D011486:Protein C; D011765:Pyruvaldehyde; D055372:AMP-Activated Protein Kinases
keywords: AMPK; APC; CHOP; Cardiomyocyte; ER stress; Methylglyoxal