Document Detail


Diabetes increases mortality after myocardial infarction by oxidizing CaMKII.
MedLine Citation:
PMID:  23426181     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Min Luo; Xiaoqun Guan; Elizabeth D Luczak; Di Lang; William Kutschke; Zhan Gao; Jinying Yang; Patric Glynn; Samuel Sossalla; Paari D Swaminathan; Robert M Weiss; Baoli Yang; Adam G Rokita; Lars S Maier; Igor R Efimov; Thomas J Hund; Mark E Anderson
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-15
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-04     Completed Date:  2013-05-13     Revised Date:  2013-12-23    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1262-74     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics,  metabolism*
Cardiac Output
Cells, Cultured
Diabetes Mellitus, Experimental / complications,  enzymology*,  mortality
Female
Fibrosis
Heart Rate
Humans
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Heart / metabolism
Myocardial Infarction / enzymology*,  etiology,  mortality
Myocardium / enzymology,  pathology
Oxidation-Reduction
Oxidative Stress
Peptides / pharmacology
Reactive Oxygen Species / metabolism
Sinoatrial Node / enzymology*,  pathology,  physiopathology
Grant Support
ID/Acronym/Agency:
R01 HL079031/HL/NHLBI NIH HHS; R01 HL113001/HL/NHLBI NIH HHS; R01 HL114893/HL/NHLBI NIH HHS; R01HL079031/HL/NHLBI NIH HHS; R01HL096652/HL/NHLBI NIH HHS; R01HL113001/HL/NHLBI NIH HHS; R01HL70250/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/AC3-I peptide; 0/Peptides; 0/Reactive Oxygen Species; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 2
Comments/Corrections
Erratum In:
J Clin Invest. 2013 May 1;123(5):2333

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