| Targeted Inhibition of Calpain Reduces Myocardial Hypertrophy and Fibrosis in Mouse Models of Type 1 Diabetes. | |
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MedLine Citation:
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PMID: 21911754 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVERecently we have shown that calpain-1 activation contributes to cardiomyocyte apoptosis induced by hyperglycemia. This study was undertaken to investigate whether targeted disruption of calpain would reduce myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.RESEARCH DESIGN AND METHODSDiabetes in mice was induced by injection of streptozotocin (STZ), and OVE26 mice were also used as a type 1 diabetic model. The function of calpain was genetically manipulated by cardiomyocyte-specific knockout Capn4 in mice and the use of calpastatin transgenic mice. Myocardial hypertrophy and fibrosis were investigated 2 and 5 months after STZ injection or in OVE26 diabetic mice at the age of 5 months. Cultured isolated adult mouse cardiac fibroblast cells were also investigated under high glucose conditions.RESULTSCalpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes. Deficiency of Capn4 or overexpression of calpastatin reduced myocardial hypertrophy and fibrosis in both diabetic models, leading to the improvement of myocardial function. These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts. In cultured cardiac fibroblasts, high glucose-induced proliferation and MMP activities were prevented by calpain inhibition.CONCLUSIONSMyocardial hypertrophy and fibrosis in diabetic mice are attenuated by reduction of calpain function. Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy. |
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Authors:
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Ying Li; Jian Ma; Huaqing Zhu; Manpreet Singh; David Hill; Peter A Greer; J Malcolm Arnold; E Dale Abel; Tianqing Peng |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-12 |
Journal Detail:
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Title: Diabetes Volume: - ISSN: 1939-327X ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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