Atorvastatin acutely reduces the reactivity to spasmogens in rat aorta: implication of the inhibition of geranylgeranylation and MYPT‐1 phosphorylation

Abstract

Statins are known to display benefits in various diseases independently from their cholesterol lowering properties. In this study, we investigated the acute effects of atorvastatin on vascular reactivity to various spasmogens in isolated rat aorta. The responses to noradrenaline (NA, 10(-8) -10(-4) m), endothelin-1 (ET-1, 10(-10) -10(-7) m), and potassium chloride (KCl, 10-100 mm) were evaluated in aortic rings pretreated with atorvastatin (10(-7) -10(-4) m, 30 min). To verify the mechanism of action, the effects of atorvastatin were studied in the presence of cholesterol precursor, mevalonate (10(-2) m, 45 min), mevalonate-derived isoprenoids, namely geranylgeranyl pyrophosphate (GGPP, 5 × 10(-6) m, 30 min) and farnesyl pyrophosphate (FPP, 5 × 10(-6) m, 30 min), and in the absence of endothelium. In parallel, aortic rings were pretreated with the specific inhibitor of Rho kinase, Y-27632 (10(-7) -10(-6) m). Atorvastatin significantly and concentration-dependently reduced the contractions to spasmogens in rat aorta. This acute inhibitory effect was also evident in endothelium-denuded rings. Pretreatment with mevalonate and GGPP, but not with FPP, reversed the inhibitory effect of atorvastatin (10(-4) m) on NA and ET-1 induced contractions. Similar to atorvastatin, pretreatment with Y-27632 inhibited the contractions to NA and KCl in a concentration-dependent manner. Western blot analysis revealed that both atorvastatin (10(-4) m) and Y-27632 (10(-6) m) pretreatment inhibited the phosphorylation of myosin phosphatase target subunit-1 (MYPT-1) triggered by NA, indicating an inhibitory influence on myosin phosphatase. In conclusion, atorvastatin displayed an acute inhibitory effect on vascular contractility evoked by various spasmogens and the inhibitory effect was possibly mediated by the inhibition of mevalonate and GGPP synthesis as well as the prevention of MYPT-1 phosphorylation induced by Rho/Rho kinase.

Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models

“…8). Other studies have identified the inhibition of the Rho/ROCK pathway and the subsequent prevention of MLC phosphorylation as the mechanism responsible for contraction inhibition by statins, adding strength to our findings (51, 57, 67–70). Statins can also affect intracellular Ca 2+ concentration, which may provide another mechanism for these effects (52, 71, 72).…”

“…More specifically, we showed that simvastatin attenuated the contraction of human myometrial smooth muscle cells alone and within an inflammatory environment stimulated by LPS. The anticontraction effect of statins has been reported in other cell types and tissues, such as vascular smooth muscle cells, aortic rings, and human endometriotic stromal cells (15, 17–19, 51, 52). Furthermore, pretreatment with simvastatin reduced the frequency of spontaneous and C5a-induced contraction of human myometrial strips, as well as in myometrial tissue collected from simvastatin-treated mice, but the effect on the intensity of the contractions was not investigated (16).…”

Mst1: Function and Mechanism in Brain and Myocardial Ischemia Reperfusion Injury

“…Similarly, another work has demonstrated that in response to oxidative stress caused by myocardial I-R injury, Mst1 is activated both in mouse myocardium in vivo and cultured cardiomyocytes [49]. In order to simulate oxidative stress during I-R, treatment of neonatal rat ventricular myocytes (NRVMs) was conducted with Hydrogen Peroxide and induced activation of MYPT-1, showing a lack of Ser696 phosphorylation of MYPT-1 indicative of its activation [53]. Previous work identified that PP1-MYPT-1 was identified as NF2 activator by dephosphorylation of Ser518 in Drosophila and in mammalian cells [54].…”