Effects of superoxide on signaling pathways in smooth muscle cells from rats.

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Abstract
Abstract —The effects of hypoxanthine and xanthine oxidase–induced superoxide anion were evaluated on various signal transduction pathways in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Superoxide increased inositol 1,4,5-tris-phosphate (IP 3 ) formation in a concentration- and time-dependent manner in both strains but more markedly in SMCs from SHR. Various antioxidants significantly decreased the superoxide-induced IP 3 formation in both strains. In addition, tyrosine kinase inhibitors, genistein and tyrphostin A25, inhibited the superoxide-induced IP 3 formation more markedly in SHR than in WKY. Moreover, superoxide decreased the basal level of cGMP to a greater extent in SHR and also suppressed the rise in cGMP induced by S -nitroso- N -acetylpenicillamine. In addition, the superoxide-induced increase in IP 3 formation was significantly inhibited by guanylyl cyclase stimulator S -nitroso- N -acetylpenicillamine but was potentiated by ODQ (a guanylyl cyclase inhibitor, 1 H -[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) and KT5823 (a cGMP-dependent protein kinase inhibitor), with a greater effect in SHR. Finally, the superoxide-enhanced IP 3 formation was not accompanied by simultaneous changes in cAMP levels, and inhibition of the adenylyl cyclase pathway did not modify the superoxide-induced IP 3 formation. Our results thus demonstrate a stimulatory effect of superoxide on IP 3 formation, mediated by the tyrosine kinase–coupled phospholipase C γ activity, and an inhibitory effect of superoxide on cGMP formation in vascular SMCs. The increased reactivity of the phospholipase C pathway and the decreased cross inhibition of the IP 3 pathway by cGMP in the presence of superoxide may underlie the altered functions of vascular SMCs in SHR.