SIMVASTATIN RELEASES CA2-SENSITIVE POOL AND INHIBITS INSP(3)-DEPENDENT CA2+ MOBILIZATION IN VASCULAR SMOOTH-MUSCLE CELLS( FROM A THAPSIGARGIN)

Simvastatin (SV), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity inhibits migration and proliferation of vascular smooth muscle cells (SMC). To investigate whether these effe cts of SV are related to inhibition of cell calcium mobilization, cult ured SMC obtained from rat aorta were loaded with Fura-2 to determine the basal cytosolic free calcium levels ([Ca2+](i)) and the agonist-st imulated Ca2+ mobilization. SV (20 mu M) transiently increased cytosol ic free calcium, an effect that depends mainly on intracellular calciu m release (68%). This effect of SV was markedly reduced (75%) by thaps igargin, an inhibitor of the Ca2+ ATPase of inositol 1,4,5-triphosphat e (InsP(3))-sensitive calcium pools. Incubation of cells with SV (15 m in) inhibited the mobilization of Ca2+ by angiotensin II, platelet-der ived growth factor, and vasopressin (IC50 = 5 mu M). SV did not affect inositol trisphosphate (InsP(3)) levels or modify its generation by a ngiotensin II (Ang II) and vasopressin. Furthermore, in saponin-permea bilized cells, SV abolished the release of calcium by 2,3-dideoxy-InsP (3)-. SV reduced the effect of thapsigargin on InsP,sensitive stores b y 67%, suggesting that SV depletes these calcium pools. The inhibitory effect of SV on calcium mobilization was prevented by coincubation of cultured cells (24 h) with 1 mM mevalonic acid, the product of HMG-Co A reductase activity. These results support the notion that SV promote s the migration and proliferation of SMC by directly affecting cell Ca 2+.