Molecular mechanisms of heme oxygenase-1 mediated cytoprotection in cardiovascular disease

Abstract

The scientific interest in gaseous molecules started in 1980 with the reports of endotheliumdependent vasorelaxation,which led to the unequivocal identification of EDRF as nitric oxide {NO) [1-3]. Since the discovery that NO acts as a potent regulator of many processes, including vascular tone, neurotransmission, inflammation, intensive investigation has followed on the role(s) of NO in inducible gene regulation[4]. A major mechanism for NO-mediated signaling effects involves the activation of soluble guanylate cyclase (sGQ, leading to enhanced cGMP formation [S}.Strikingly however, it was known for a longer time, that cells can produce another endogenous gaseous molecule by an enzymatic reaction initially described by Tenhunen and Schmid in 1968: the catalytic breakdown of heme by the microsomal heme oxygenase (HO) enzyme system which releases carbon monoxide (CO) [6,7]. In the past decade, the interest in HO isozymes shifted from their metabolic function of heme degradation to another critical physiological function as a cytoprotective chaperone in numerous models of cellular stress [4, 8]. Heme oxygenases catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and generate equimolar amounts of biliverdin, iron and carbon monoxide (CO).