Nitric oxide induces heme oxygenase-1 expression in vascular smooth muscle cells

We have recently reported that vascular smooth muscle cells (SMC) generate guanylate cyclase-stimulatory carbon monoxide (CO) by the action of heme oxygenases (HO). Since nitric oxide (NO) is an important signaling molecule in regulating SMC function, we examined whether NO could modulate the expression of HO by rat aortic SMC. Treatment of SMC with the NO donors sodium nitroprusside, sin-1, or S-nitroso-n-acetyl-penicillamine resulted in a concentration- and timedependent increase in the levels of HO-1 mRNA and protein while the expression of HO-2 remained unchanged. NO donors elevated HO-1 mRNA within 1 hour and protein levels 4 hours following treatment, and the levels of HO-1 transcript and protein progressively increased over 24 hours. Both actinomycin D and cycloheximide abolished the NOinduced rise in HO-1 protein. The membrane-permeable cGMP analogue 8-bromo cGMP minimally increased HO-1 mRNA and protein. These results demonstrate that NO stimulates the expression of the HO-1 gene in vascular SMC. The induction of the HO-1 gene depends on de novo RNA and protein synthesis and occurs primarily via a cGMPindependent pathway. The ability of NO to stimulate HO-1 expression and the consequent release of guanylate cyclase-stimulatory CO from SMC may represent a novel mechanism by which NO can regulate vascular tone and platelet reactivity at sites of vessel wall iniurv.