title: Diabetes increases mortality after myocardial infarction by oxidizing CaMKII.
abstract: Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Min
authors: M
authors: Luo
authors: Xiaoqun
authors: X
authors: Guan
authors: Elizabeth D
authors: ED
authors: Luczak
authors: Di
authors: D
authors: Lang
authors: William
authors: W
authors: Kutschke
authors: Zhan
authors: Z
authors: Gao
authors: Jinying
authors: J
authors: Yang
authors: Patric
authors: P
authors: Glynn
authors: Samuel
authors: S
authors: Sossalla
authors: Paari D
authors: PD
authors: Swaminathan
authors: Robert M
authors: RM
authors: Weiss
authors: Baoli
authors: B
authors: Yang
authors: Adam G
authors: AG
authors: Rokita
authors: Lars S
authors: LS
authors: Maier
authors: Igor R
authors: IR
authors: Efimov
authors: Thomas J
authors: TJ
authors: Hund
authors: Mark E
authors: ME
authors: Anderson
mesh_terms: D000818:Animals; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002302:Cardiac Output; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology* / Q000401:mortality; D005260:Female; D005355:Fibrosis; D006339:Heart Rate; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009203:Myocardial Infarction / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012849:Sinoatrial Node / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology
chemical_list: C527819:AC3-I peptide; D010455:Peptides; D017382:Reactive Oxygen Species; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2