Abstract 1341: Insulin-Like Growth Factor I Deficiency Prolongs Survival and Antagonizes Paraquat-Induced Cardiomyocyte Dysfunction: Reactive Oxygen Species and Aging Gene in Heart
Organismal longevity has a genetic component and aging is a regulated process. 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 survival rate, cardiomyocyte viability, contractile function and aging related gene expression change underlying severe IGF-1 deficiency in response to challenge with the severe oxidative inducer-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 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 significant 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 (48 hrs) reduced PS, ± dL/dt, tolerance to high stimulus frequency, resting and rise in intracellular Ca2+, as well as prolonged TR90, all of which were nullified or masked by IGF-1 deficiency. Paraquat increased reactive oxygen species and carbonyl production, the effects of which were nullified or masked by IGF-1 deficiency. Expression of the anti-aging gene Klotho transcription factor Foxo3a was up- and down-regulated, respectively, in LID mice. Transfection of dominant negative Foxo3a prolonged cardiomyocyte survival in response to paraquat or H2O2, associated with a reduction I IGF-I secretion. These data suggested that IGF-1 deficiency regulated cardiomyocyte longevity through foxo3a and possibly klotho.