We intend to investigate the participation of vascular heme oxygenase (HO) isoenzymes (HO-1, HO-2) in the regulation of the renal vasculature in normotensive and hypertensive rats. HO-1 and HO-2 catalyze the breakdown of heme to carbon monoxide (CO), a vasodilator and antiapoptotic factor, and biliverdin/bilirubin, antioxidants that act to countervail oxidative stress injury. We have obtained evidence that HO-1 is key factor to the defense of the endothelium; its activity improves vascular function and ameliorates both genetic and experimental forms of hypertension. We hypothesize that overexpression of HO-1 leads to a persistent decrease in angiotensin II (Ang II)-mediated oxidative stress. Further, suppression of HO activity by diminishing HO-1 and/or HO-2 expression should produce endothelial dysfunction; namely, endothelial cell sloughing, oxidant generation, expression of inflammatory molecules and increased vascular reactivity to pressor agonists. These hypotheses will be tested in vitro and in vivo in models of genetic and experimental hypertension with molecular genetic probes (retroviral/lentiviral vectors), namely: 1) Targeting HO-1 and HO-2 expression to define their roles and to explore their mechanisms of action in protecting the endothelium from Ang II-induced injury; 2) Determining the effect of genetic interventions, which selectively alter HO-1 or HO-2 expression on endothelial function in HO-1 transgenic rats and HO-2 knockout mice; 3) Examining whether overexpression of HO-1 protects endothelial function and attenuates the development of hypertension in the SHR and in renovascular lesions. If so, the mechanism of action will be sought; 4) Determining whether targeting of the endothelium with HO-1 is sufficient to offset Ang II-induced vascular injury. This proposal will allow, for the first time, an in-depth analysis of the function of HO-1 and HO-2 in a relatively normal setting, without germ line manipulation. If the anticipated beneficial vascular actions of the HO system are correct, then these findings may be applied to the development of innovative therapies based on gene targeting for the treatment of hypertension and cardiovascular disease.
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