title: Metformin differentially activates ER stress signaling pathways without inducing apoptosis.
abstract: Endoplasmic reticulum stress signaling (ERSS) plays an important role in the pathogenesis of diabetes and heart disease. The latter is a common comorbidity of diabetes and worsens patient outcome. Results from clinical studies suggest beneficial effects of metformin - a widely used oral drug for the treatment of type 2 diabetes - on the heart of diabetic patients with heart failure. We therefore analyzed the effect of metformin on ERSS in primary rat cardiomyocytes. We found that metformin activates the PERK-ATF4 but not the ATF6 or IRE1-XBP1 branch in ERSS and leads to a strong upregulation of CHOP mRNA and protein. Surprisingly, long-term induction of CHOP by metformin is not accompanied by apoptosis even though CHOP is regarded to be a mediator of ER-stress-induced apoptosis. In conclusion, metformin induces distinct ER stress pathways in cardiomyocytes and our results indicate that CHOP is not necessarily a mediator of apoptosis. Metformin might exert its cardioprotective effect through selective activation of ERSS pathways in the cardiomyocyte.
authors: Department of Pediatric Cardiology and Pediatric Intensive Care Medicine, University of Göttingen, Göttingen, Germany. thomas.quentin@med.uni-goettingen.de
authors: Thomas
authors: T
authors: Quentin
authors: Michael
authors: M
authors: Steinmetz
authors: Andrea
authors: A
authors: Poppe
authors: Sven
authors: S
authors: Thoms
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D006331:Heart Diseases / Q000150:complications / Q000517:prevention & control; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat