title: CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction.
abstract: Epidemiological studies indicate that methylglyoxal (MGO) plasma levels are closely linked to diabetes and the exacerbation of diabetic cardiovascular complications. Recently, it was established that endoplasmic reticulum (ER) stress importantly contributes to the pathogenesis of diabetes and its cardiovascular complications. The objective of this study was to explore the mechanism by which diabetes instigates cardiomyocyte apoptosis and cardiac dysfunction via MGO-mediated myocyte apoptosis. Intriguingly, the MGO activated unfolded protein response pathway accompanying apoptotic events, such as cleavages of PARP-1 and caspase-3. In addition, Western blot analysis revealed that MGO-induced myocyte apoptosis was inhibited by depletion of CHOP with siRNA against Ddit3, the gene name for rat CHOP. To investigate the physiologic roles of CHOP in vivo, glucose tolerance and cardiac dysfunction were assessed in CHOP-deficient mice. No significant difference was observed between CHOP KO and littermate naïve controls in terms of the MGO-induced impairment of glucose tolerance. In contrast, myocyte apoptosis, inflammation, and cardiac dysfunction were significantly diminished in CHOP KO compared with littermate naïve controls. These results showed that CHOP is the key signal for myocyte apoptosis and cardiac dysfunction induced by MGO. These findings suggest a therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy.
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Dae-Hwan
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Anatomy, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: Department of Cardiology, Pulmonology and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.affiliation: Department of Microbiology, Ewha Womans University School of Medicine, 911-1 Mok-dong, Seoul, Republic of Korea.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Division of Cardiovascular and Rare Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Cheongju-si, Chungcheongbuk-do, Republic of Korea.
authors.forename: Geun-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea. Electronic address: changhoon_woo@yu.ac.kr.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D011765:Pyruvaldehyde / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C497251:Ddit3 protein, rat; D051742:Transcription Factor CHOP; D011765:Pyruvaldehyde
keywords: CHOP; Cardiac dysfunction; Diabetes; ER stress; Methylglyoxal