Regulation and Effects of Heme-Oxygenase-1 Expression in Chronic Inflammation.

Abstract

Heme oxygenase-1 (HO-1) enzyme plays critical role in metabolizing the excess heme generated during hemolysis in pathological conditions, such as sickle cell disease. We and others have previously demonstrated that during chronic intravascular hemolysis the expression of HO-1 protein is not sufficient to reduce the oxidative burden of free heme in the vasculature, leading to oxidative stress and vascular inflammation. This proposal examined two areas critical to the understanding of HO-1 expression and function during inflammation: the role of post-transcriptional regulation in control of protein expression and the importance of its by-product carbon monoxide (CO) in mediating anti-inflammatory, anti-apoptotic effects. The research utilized a murine sickle model which has perturbations of heme catabolism leading to oxidative stress and inflammation. Studies in this model will test whether HO-1, or its by-products, can therapeutically alter the natural history of sickle cell disease. In addition, cell culture models in which heme levels are controlled were used to explore microRNA regulation of heme oxygenase-1 (HO-1) expression. Combined these experimental endeavors aim to identify new aspects of HO-1 research.