Reduced Cardiotropic Response To Insulin In Spontaneously Hypertensive Rats: Role Of PPARgamma-initiated Signaling

Background: Vascular insulin resistance has been shown to play a pathogenic role in the development of spontaneous hypertension. However, it remains unclear whether there exists cardiac insulin resistance in spontaneous hypertension. The present study attempted to determine whether the inotropic response to insulin is impaired in hypertensive myocardium, and if so, to investigate the mechanisms involved.Methods and Results: Single ventricular myocytes were enzymatically isolated and myocyte shortening and intracellular Ca²⁺ transients in response to insulin were assessed (n=15-22 myocytes from 6-8 hearts/group) with a video-based motion edge-detection system. Blood glucose and plasma insulin were increased in SHR compared with those in age- and sex-matched WKY (n=8, P<0.05). In addition, SHR myocytes exhibited remarkable decrease in the positive inotropic response to insulin (10-7 mol/L) as evidenced by reduced peak twitch amplitude (% of cell baseline, 7.8 %±0.6 % vs. 10.2 %±0.5 % of WKY+insulin, P<0.05) and Ca2+ transient amplitude (0.27±0.02 vs. 0.47±0.05 of WKY+insulin, P<0.05). Moreover, myocardial PPARγand phosphatidylinositol 3-kinase (PI3K) p85 expressions, especially, insulin-induced Akt phosphorylation were reduced by 26.5%, 39.6% and 42.3% respectively in SHR (n=3, P<0.05 vs. WKY), which were partially restored when rats were treated with rosiglitazone (RSG, 3 mg·kg^-1·d^-1) for 14 days. RSG treatment also reduced blood glucose and plasma insulin in SHR (n=8, P<0.01), and restored the myocyte inotropic response to insulin (P<0.05 vs. before RSG). Pretreatment with an Akt inhibitor almost abolished the insulin-induced inotropic effect and calcium transient changes in both WKY and RSG-treated SHR cardiomyocytes (P<0.05).Conclusion: These data demonstrate, for the first time, that there exists myocardial insulin resistance in SHR. The decreased PPARγexpression and subsequent impairment in PI-3 kinase/Akt signaling plays a causative role in the impaired inotropic response to insulin in SHR heart. The present findings also suggest that insulin resistance may not only play a role in the development of hypertension as previously reported, but also contribute directly to the development of heart failure in SHR.