Insulin-Like Growth Factor I Deficiency Prolongs Survival and Antagonizes Paraquat–Induced Cardiomyocyte Dysfunction: Role of Oxidative Stress
Abstract
Interruption of insulin-like growth factor I (IGF-1) signaling has been demonstrated to prolong life span although the underlying mechanism has not been elucidated. The aim of this study was to examine the influence of severe IGF-1 deficiency on survival rate, cardiomyocyte viability, contractile function, and intracellular Ca2+ property in response to challenge with the pro-oxidant paraquat. C57 negative and liver IGF-1 deficient (LID) transgenic mice were administrated paraquat (75 mg/kg) and survival was monitored. LID mice displayed a significantly improved survival than did C57 mice evaluated by the Kaplan-Meier curve. MTT assay revealed that in vitro IGF-1 treatment significantly sensitized paraquat-induced cell death in both C57 and LID groups, with significantly better cell viability in LID cardiomyocytes. Compared to C57 mouse cardiomyocytes, LID myocytes displayed reduced peak shortening (PS), decreased maximal velocity of shortening/relengthening (± dL/dt), prolonged time-to-90% relengthening (TR90), and comparable tolerance to high stimulus frequency and intracellular Ca2+ homeostasis. Paraquat treatment for 48 hours reduced PS, ± dL/dt, tolerance to high stimulus frequency, resting and rise in intracellular Ca2+, and prolonged TR90, all of which were nullified or masked by IGF-1 deficiency. Paraquat increased reactive oxygen species and carbonyl production upregulated the Ca2+ regulating protein SERCA2a, and downregulated Na+ -Ca2+ exchanger, the effects of which were nullified or masked by IGF-1 deficiency. Although LID mice displayed reduced whole body glucose clearance, cardiomyocytes from LID mice exhibited dramatically enhanced insulin-stimulated phosphorylation of insulin receptor and Akt. These data demonstrated that IGF-1 deficiency may antagonize or mask the paraquat-induced decrease in survival, cardiomyocyte dysfunction, oxidative stress, and change in Ca2+ regulating proteins.
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Mary Ann Liebert, Inc.
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Published online: 25 December 2007
Published in print: December 2007
Published ahead of print: 2 November 2007
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