| Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. | |
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MedLine Citation:
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PMID: 22326951 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The leading cause of death in diabetic patients is cardiovascular disease; diabetic cardiomyopathy is typified by alterations in cardiac morphology and function, independent of hypertension or coronary disease. However, the molecular mechanism that links diabetes to cardiomyopathy is incompletely understood. Insulin resistance is a hallmark feature of diabetes, and the FoxO family of transcription factors, which regulate cell size, viability, and metabolism, are established targets of insulin and growth factor signaling. Here, we set out to evaluate a possible role of FoxO proteins in diabetic cardiomyopathy. We found that FoxO proteins were persistently activated in cardiac tissue in mice with diabetes induced either genetically or by high-fat diet (HFD). FoxO activity was critically linked with development of cardiomyopathy: cardiomyocyte-specific deletion of FoxO1 rescued HFD-induced declines in cardiac function and preserved cardiomyocyte insulin responsiveness. FoxO1-depleted cells displayed a shift in their metabolic substrate usage, from free fatty acids to glucose, associated with decreased accumulation of lipids in the heart. Furthermore, we found that FoxO1-dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance. Together, these data suggest that activation of FoxO1 is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease. |
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Authors:
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Pavan K Battiprolu; Berdymammet Hojayev; Nan Jiang; Zhao V Wang; Xiang Luo; Myriam Iglewski; John M Shelton; Robert D Gerard; Beverly A Rothermel; Thomas G Gillette; Sergio Lavandero; Joseph A Hill |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-02-13 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-03-01 Completed Date: 2012-04-30 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 1109-18 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8573, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Body Weight Cell Size Cell Survival Diabetic Cardiomyopathies / metabolism Fatty Acids / metabolism Forkhead Transcription Factors / metabolism* Glucose / metabolism Heart Failure / metabolism Insulin / metabolism Mice Mice, Inbred C57BL Myocytes, Cardiac / metabolism Rats Rats, Sprague-Dawley Signal Transduction Somatomedins / metabolism Subcellular Fractions |
| Grant Support | |
ID/Acronym/Agency:
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HL 097768/HL/NHLBI NIH HHS; HL-072016/HL/NHLBI NIH HHS; HL-075173/HL/NHLBI NIH HHS; HL-080144/HL/NHLBI NIH HHS; HL-090842/HL/NHLBI NIH HHS; R01 HL072016-10/HL/NHLBI NIH HHS; R01 HL097768/HL/NHLBI NIH HHS; U01 HL100401/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/Insulin; 0/Somatomedins; 50-99-7/Glucose |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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