Heme oxygenase-1 protects against vascular constriction and proliferation

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated i n systemic inflammatory conditions by oxidant stress. Vascular injury is ch aracterized by a local reparative process with inflammatory components, ind icating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell pr oliferation during vascular injury. Expression of HO-1 in arteries stimulat ed vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21(Cip1). HO-1 re duced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1(-/-) mice produce d hyperplastic arteries compared with controls. Induction of the HO-1 pathw ay moderates the severity of vascular injury by at least two adaptive mecha nisms independent of nitric oxide, and is a potential therapeutic target fo r diseases of the vasculature.