Heme oxygenase-1 protects against vascular constriction and proliferation

Abstract

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated 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 p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1−/− mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.

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Figure 1: HO-1 expression induces vascular relaxation mediated by a cGMP-dependent mechanism.
Figure 2: Endogenous HO-1 expression in normal and injured arteries.
Figure 3: HO-1 expression limits cell proliferation and lesion formation after arterial injury.
Figure 4: Cell growth and cell-cycle distribution in pig VSMCs in response to HO-1 expression.
Figure 5: Deletion of Hmox1 results in enhanced cell growth and facilitates G1/S transition.
Figure 6: Vascular lesion formation in Hmox1−/− mice.

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Acknowledgements

H.J.D. was supported by a grant from NATO (NWO) and the Intercardiologisch Instituut Nederland (ICIN).

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Correspondence to Elizabeth G. Nabel.

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