Heme oxygenase and carbon monoxide in endothelial cell biology

The realization that endogenous small gas molecules can serve critical functions in vascular biology originated in the 1980s, with the identification of the endothelial cell (EC)-derived relaxing factor as equivalent to the gas nitric oxide (NO), a potent endogenous relaxant of vascular smooth muscle (1–2). NO arises from the enzymatic conversion of L-arginine to L-citrulline, by the action of constitutive and inducible NO synthase (NOS) enzymes (3). The production of NO by endothelial NOS (eNOS) provides an essential component of EC function in the regulation of vascular processes, including vascular tone, as well as the inhibition of platelet aggregation, leukocyte adherence, and smooth muscle cell (SMC) proliferation (Reviewed in Ref. 4, 5). On the other hand, the vasoactive properties of carbon monoxide (CO) have long been recognized in the context of accidental inhalation exposure. CO binds avidly to hemoglobin, with an affinity 250 times that of oxygen, and therefore causes tissue hypoxia and ultimately death at high concentration. In the mid-twentieth century, Sjostrand and later Coburn and colleagues identified the endogenous occurrence of CO in human blood as the consequence of hemoglobin turnover (6–7). The enzymatic mechanism for the endogenous production of CO from heme degradation was identified as early as 1968, with the initial characterization of microsomal heme oxygenase (8–9), which converts heme to equimolar biliverdin-IXα, CO, and free iron. The reaction requires nicotinamide adenine dinucleotide phosphate (NADPH):cytochromep450 reductase as a source of reducing equivalents, andNADPH:biliverdin reductase (BVR) to convert biliverdin-IXα to bilirubin-IXα. Until the discovery of NO, and the elucidation of its roles in vascular signaling, endogenous CO was regarded by the scientific community as a waste product of metabolism.