The inducible isoform of heme oxygenase (HO-1) catalyzes the degradation of heme to biliverdin, iron and carbon monoxide (CO). Activation of HO-1 provides cytoprotection and serves as an adaptive defense mechanism in many systems. We have identified and characterized HO-1 in vascular cells and have obtained several lines of evidence that suggest that endogenous CO, generated by HO-mediated heme catabolism in vascular cells, plays a unique and important physiological role in the circulation and in the pathophysiological process of vessel wall remodeling that occurs in response to vascular injury. Therefore, the basic hypothesis of this proposed project is that HO-1 activation and its CO product are critical regulators of the vessel wall's response to injury. The major objectives of this study are to (a) define the role of the HO/CO system and its molecular mechanisms in the pathophysiology of vascular remodeling, and (b) apply these concepts to investigate the HO/CO system as a novel therapeutic target to modify the vascular response to injury. To test our hypothesis and achieve the stated objectives, we plan to pursue the following four complementary and linked specific aims. First, we will elucidate the mechanism(s) of control of vascular cell growth by heme oxygenase and CO in vitro, primarily using cultured vascular smooth muscle and endothelial cells in which HO-1 is overexpressed by adenovirus-mediated transfer of the HO-1 gene. Second, we will determine how CO inhibits platelet adhesion and activation. Third, we plan to study the actions of heme oxygenase and CO on the response to vascular injury in vivo, using arterial injury models in transgenic mice deficient in HO-1. Finally, we will investigate heme oxygenase and CO as potential therapeutic targets in vascular injury, using both pharmacologic and HO-1 gene transfer approaches. It is anticipated that this project will elucidate the role and molecular mechanisms of the HO/CO system in the pathophysiology of the vascular response to injury, with the aim of applying these basic concepts to develop the HO/CO system as a novel target for the treatment of vascular disease.
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