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Heme oxygenase-1 protects against vascular constriction and proliferation

Nature Medicine volume 7, pages 693–698 (2001)Cite this article

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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Authors and Affiliations

  1. Vascular Biology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA

    Henricus J. Duckers, Manfred Boehm, Andrea L. True, Hong San & Elizabeth G. Nabel

  2. Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, USA

    Gary J. Nabel

  3. Department of Physiology, Medical College of Georgia, Augusta, Georgia, USA

    James L. Park & R. Clinton Webb

  4. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Shaw-Fang Yet & Mu-En Lee

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Correspondence to Elizabeth G. Nabel.

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Duckers, H., Boehm, M., True, A. et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 7, 693–698 (2001). https://doi.org/10.1038/89068

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