title: 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 Ca(2+) 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 (TR(90)), and comparable tolerance to high stimulus frequency and intracellular Ca(2+) homeostasis. Paraquat treatment for 48 hours reduced PS, +/- dL/dt, tolerance to high stimulus frequency, resting and rise in intracellular Ca(2+), and prolonged TR(90), all of which were nullified or masked by IGF-1 deficiency. Paraquat increased reactive oxygen species and carbonyl production upregulated the Ca(2+) regulating protein SERCA2a, and downregulated Na(+) -Ca(2+) 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 Ca(2+) regulating proteins.
authors.affiliation: Division of Pharmaceutical Sciences, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Nair
authors.initials: N
authors.lastname: Sreejayan
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005951:Glucose Tolerance Test; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D007334:Insulin-Like Growth Factor I; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D010269:Paraquat; D002118:Calcium