期刊
HYPERTENSION
卷 59, 期 3, 页码 680-U349出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.111.181867
关键词
IGF-1; high fat; heart; oxidative stress; insulin signaling; mitochondrial function
资金
- American Heart Association Pacific Mountain Affiliate [0355521Z]
- American Diabetes Association [7-08-RA-130]
- National Science Foundation of China [30728023]
Obesity is often associated with reduced plasma insulin-like growth factor 1 (IGF-1) levels, oxidative stress, mitochondrial damage, and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high-fat diet-induced oxidative, myocardial, geometric, and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low-(10%) or high-fat (45%) diet to induce obesity. High-fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin 6, insulin, and triglyceride, as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end-systolic and end-diastolic diameter, increased wall thickness, and cardiac hypertrophy in high-fat-fed FVB mice. High-fat diet promoted reactive oxygen species generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation (including depressed peak shortening and maximal velocity of shortening/relengthening), prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor and postreceptor signaling molecules insulin receptor substrate 1 (tyrosine/serine phosphorylation), Akt, glycogen synthase kinase 3 beta, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and uncoupling protein 2. Intriguingly, IGF-1 mitigated high-fat-diet feeding-induced alterations in reactive oxygen species, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling, and insulin signaling but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high-fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high-fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly because of preserved cell survival, mitochondrial function, and insulin signaling. (Hypertension. 2012; 59: 680-693.). Online Data Supplement
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