Pravastatin normalizes endothelium-derived contracting factor-mediated response via suppression of Rho-kinase signalling in mesenteric artery from aged type 2 diabetic rat.
OBJECTIVE
Although pravastatin has known pleiotropic effects against adverse cardiovascular conditions, little is known about its effects on endothelium-derived contracting factor (EDCF)-mediated signalling. We aimed to determine the effects of pravastatin on the production of and responses to EDCF in superior mesenteric arteries isolated from rats at the chronic stage of type 2 diabetes.


METHODS
Contractions to acetylcholine (ACh) were examined in superior mesenteric artery rings from aged type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats (56-60 weeks old), from control age-matched non-diabetic Long-Evans Tokushima Otsuka (LETO) rats and from pravastatin-treated (10 mg kg(-1) , p.o., daily for 4 weeks) OLETF rats. Mesenteric artery expressions of cyclo-oxygenases (COXs), microsomal-PGE synthases (mPGESs), RhoA and Rho-kinase proteins, and also the level of phosphorylated ezrin, radixin and moesin (PERM), a substrate for Rho-kinase, were detected by Western blotting.


RESULTS
Arteries from OLETF rats exhibited (vs. LETO rats) (1) enhanced ACh-induced EDCF-mediated contractions, which were inhibited by the Rho-kinase inhibitor Y27632, (2) reductions in the ACh-stimulated release of both PGE(2)  and superoxide and (3) increased COX-1 and PERM protein expressions. Mesenteric arteries from OLETF rats treated with pravastatin exhibited (vs. untreated OLETF) (1) reduced ACh-induced contraction, (2) suppressed ACh-induced PGE(2)  production and superoxide generation and (3) reduced ACh-induced PERM protein expression.


CONCLUSIONS
These results suggest that pravastatin exerts beneficial effects against abnormal EDCF signalling by suppressing Rho-kinase and promoting antioxidant activity in the mesenteric arteries of rats at the chronic stage of type 2 diabetes.
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
K
K
Ishida
T
T
Matsumoto
K
K
Taguchi
K
K
Kamata
T
T
Kobayashi
D000375:Aging / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D020334:Rats, Inbred OLETF; D015398:Signal Transduction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054460:rho-Associated Kinases; D017035:Pravastatin