Pravastatin normalizes ET-1-induced contraction in the aorta of type 2 diabetic OLETF rats by suppressing the KSR1/ERK complex

Shingo Nemoto, Kumiko Taguchi, Takayuki Matsumoto, Katsuo Kamata, Tsuneo Kobayashi
American Journal of Physiology. Heart and Circulatory Physiology 2012 October 1, 303 (7): H893-902
Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. In the present study, we hypothesized that treatment with pravastatin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) would normalize the ET-1-induced contraction in aortas isolated from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Contractile responses were examined by measuring isometric force in endothelium-denuded aortic helical strips from four groups: Long-Evans Tokushima Otsuka (LETO; genetic control), OLETF (type 2 diabetic), pravastatin-treated LETO, and pravastatin-treated OLETF rats. Both immunoblot analysis and immunoprecipitation assays were used to examine Src, protein phosphatase (PP)2A, kinase suppressor of Ras (KSR)1, and ERK signaling pathway protein levels and activities. In endothelium-denuded aortas isolated from OLETF rats at the chronic stage of diabetes (56-60 wk) (vs. those from age-matched LETO rats), we found the following: 1) ET-1-induced contraction was enhanced, 2) ERK1/2 phosphorylation was increased, 3) phosphorylations of KSR1 and PP2A were reduced (i.e., enhancement of the kinase active state), 4) ERK1/2-KSR1 complexes were increased, and 5) Src tyrosine kinase activity was diminished. Endothelium-denuded aortas isolated from OLETF rats treated with pravastatin (10 mg/kg po, daily for 4 wk) exhibited normalized ET-1-induced contractions and suppressed ET-1-stimulated ERK phosphorylation, with the associated phosphorylated KSR1 and phosphorylated PP2A levels being increased toward normal levels. These results suggest that in type 2 diabetic rats, pravastatin normalizes ET-1-induced contraction in aortic smooth muscle via a suppression of PP2A/KSR1/ERK activities after an enhancement of Src kinase activity.

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