HO-1 and Vascular Occlusion

The beneficial actions of HO-1 following arterial injury are mediated, in part, by its ability to suppress vascular smooth muscle cell proliferation. Induction or gene delivery of HO-1 in cultured vascular smooth muscle cells blocks cell growth and DNA synthesis. In addition, vascular smooth muscle cells derived from HO-1-null mice display enhanced growth and DNA synthesis compared to cells obtained from wild-type animals. Moreover, greater smooth muscle cell proliferation is observed in arterial lesions from HO-1-deficient mice compared to wild-type animals, confirming the anti-proliferative effect of HO-1 in vivo. The anti-proliferative action of HO-1 is mediated through the soluble guanylate cyclase/cGMP pathway since inhibition of soluble guanylate cyclase or protein kinase G restores cell growth. The exogenous administration of CO or bilirubin also inhibits vascular smooth muscle cell proliferation, cell cycle progression, DNA synthesis, and the expression of cell cycle regulatory proteins, suggesting a role for both of these products in the anti-proliferative action of HO-1. More recently, HO-1 has also been demonstrated to inhibit vascular smooth muscle cell migration via the CO-mediated inhibition of Nox1 enzyme activity and downstream redox-sensitive pro-migratory pathways. Interestingly, HO-1 stimulates cell cycle progression and proliferation in vascular endothelium. Transduction of the HO-1 gene into endothelial cells promotes their growth and the development of capillary-like tube structures while inhibition or deletion of HO-1 blocks endothelial cell growth. HO-1 also facilitates endothelial cell proliferation, migration and capillary sprout formation in response to specific angiogenic factors. In addition, HO-1 promotes the re-endothelialization of injured arteries. HO-1 enhances re-endothelialization by promoting the mobilization and homing of endothelial progenitor cells to sites of injury, and moreover, the expression of HO-1 by endothelial progenitor cells is required for their incorporation into blood vessels.

The HO-1-mediated increase in endothelial regrowth following arterial injury is dependent on the induction of stromal cell-derived factor-1 and vascular endothelial growth factor, and is mimicked by the inhalation of CO, suggesting a key role for this gas in repairing endothelium-denuded areas of blood vessels. HO-1 may also preserve blood vessel patency by inhibiting thrombosis. HO-1 deficiency accelerates arterial thrombus formation following photochemical injury and increases thrombus size in a murine model of deep vein thrombosis. The anti-thrombotic actions of HO-1 are likely mediated by CO and biliverdin, since the exogenous administration of either compound rescues HO-1-deficient animals from thrombosis. Both of these HO-1 products may prevent intravascular thrombosis by ameliorating endothelial cell damage. In addition, HO-1-derived CO may block thrombosis by inhibiting platelet aggregation and the expression of plasminogen activator inhibitor-1 and tissue factor.