Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes.
Diabetic cardiomyopathy is characterized by cardiac dysfunction and altered level/function of insulin-like growth factor I (IGF-I). Both endogenous and exogenous IGF-I have been shown to effectively alleviate diabetes-induced cardiac dysfunction and oxidative stress. This study was designed to examine the effect of cardiac overexpression of IGF-I on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse myocytes. Both IGF-I heterozygous transgenic mice and their wild-type FVB littermates were made diabetic with a single injection of STZ (200 mg/kg, i.p.) and maintained for 2 weeks. The following mechanical indices were evaluated in ventricular myocytes: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/- dL/dt). Intracellular Ca2+ was evaluated as resting and peak intracellular Ca2+ levels, Ca2+-induced Ca2+ release and intracellular Ca2+ decay rate (tau). STZ led to hyperglycemia in FVB and IGF-I mice. STZ treatment prolonged TPS and TR90, reduced Ca2+-induced Ca2+ release, increased resting intracellular Ca2+ levels and slowed tau associated with normal PS and +/- dL/dt. All of which, except the elevated resting intracellular Ca2+, were prevented by the IGF-I transgene. In addition, myocytes from STZ-treated FVB mice displayed an attenuated contractile response to the beta-adrenergic agonist isoproterenol, which was restored by the IGF-I transgene. Contractile response to the alpha-adrenergic agonist phenylephrine and angiotensin II was not affected by either STZ treatment or IGF-I. These results validate the beneficial role of IGF-I in diabetic cardiomyopathy, possibly due to an improved beta-adrenergic response.
Norby
F L
FL
Division of Pharmaceutical Sciences, University of Wyoming College of Health Sciences, Laramie, Wyoming 82071, USA.
Aberle
N S
NS
Kajstura
J
J
Anversa
P
P
Ren
J
J
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression; D006352:Heart Ventricles; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009929:Organ Size; D010656:Phenylephrine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D000804:Angiotensin II; D010656:Phenylephrine; D007334:Insulin-Like Growth Factor I; D007545:Isoproterenol; D002118:Calcium