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• _7 value "Some of the cholesterol-independent beneficial effects of statins, 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, in preventing cardiovascular disease may be due to their antithrombotic properties. Thrombin induces vascular smooth muscle cell (VSMC) proliferation, a primary determinant of atherosclerotic lesion progression. To investigate whether the antithrombotic effects of statins extends to inhibition of cell proliferation, we studied the effect of mevastatin on thrombin-induced rat vascular smooth muscle cell growth. Mevastatin (1 ?M) significantly inhibited thrombin-induced DNA synthesis in rat VSMC and this effect was not due to induction of apoptosis. Thrombin-induced mitogen-activated protein (MAP) kinase activities such as those of extracellular signal-regulated kinase2 (ERK2), Jun N-terminal kinase1 (JNK1) and p38 MAP kinase were significantly inhibited by mevastatin. However, the inhibitory effect was greater on JNK1 and p38 MAP kinase activities than on ERK2 activity. Mevalonate (500 ?M) attenuated the inhibitory effect of mevastatin on thrombin-induced DNA synthesis and MAP kinase activities. Thrombin increased ras and rac1 activities in a time-dependent manner and mevastatin inhibited these activities. Consistent with the inhibition of rac1, mevastatin also inhibited thrombin-induced superoxide production. Exogenous mevalonate reversed the inhibitory effect of mevastatin on thrombin-induced rac1 activation and superoxide production. Mevastatin inhibited thrombin-induced JAK2 and STAT3 tyrosine phosphorylation supporting our earlier results that reactive oxygen species (ROS) mediate the activation of JAK-STAT pathway by thrombin in these cells. Consistent with the role of ROS in thrombin-induced VSMC growth, mevastatin also inhibited ROS mediated transactivation of EGFR receptor induced by thrombin. Together, these results suggest that the antiatherosclerotic effects of statins include inhibition of VSMC proliferation induced by thrombin and this effect is mediated via abrogation of ROS generation." provenance.
• _7 wasQuotedFrom _6 provenance.