Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice

Background-Increasing evidence supports the role of heme oxygenase-1 (HO-1) in cytoprotective response and iron homeostasis. The object of this study was to investigate whether adenovirus-mediated gene transfer of HO-1 in art eries reduces iron overload and inhibits lesion formation in apolipoprotein E (apoE)-deficient mice. Methods and Results-Infection of rat aortic smooth muscle cells with adenov irus carrying the human HO-1 gene (Adv-HO-1) resulted in a high-level expre ssion of HO-1 protein, which effectively reduced the hemin-induced iron ove rload in these cells. Adenovirus-mediated gene transfer in arteries in vivo was achieved by direct injection of Adv-HO-1 into the left ventricles of a nesthetized animals. Transgene was expressed in the endothelium. and aortic lesion of apoE-deficient mice after they had received recombinant adenovir us for I week and gradually decayed during the next 5 weeks. When young apo E-deficient mice (14 weeks old) received Adv-HO-1 (2.5X10(9) pfu) for 6 wee ks, lesions that developed in the aortic root or aortic arch were significa ntly smaller than those in control littermates receiving empty viral vector . Furthermore, the iron deposition as well as tissue iron content was much less in aortic tissue of Adv-HO-1-treated mice. The inhibitory effect of HO -1 gene transfer on the progression of advanced lesions was also observed i n older apoE-deficient mice (20 weeks old) receiving Adv-HO-1 intraventricu larly. Conclusions-Overexpression of HO-1 in vascular cells facilitates iron metab olism and attenuates development of atherosclerosis in apoE-deficient mice.