Heme Oxygenase-1 and Carbon Monoxide in Vascular Regulation

Abstract

The gaseous signaling molecules nitric oxide (NO) and carbon monoxide (CO), which are generated endogenously by the heme oxygenase (HO) and nitric oxide synthase (NOS) systems, respectively, play significant roles in the regulation of vascular function. The HO enzymes exist in both constitutive (HO-2, HO-3) and inducible (HO-1) isoforms, the latter identified as a component of the cellular stress response. HO converts heme to CO, biliverdin, and iron; and these metabolites may all contribute to the apparent cytoprotective effects of HO. Like NO, CO has potent vasodilator properties, and may regulate other vascular functions such as the aggregation of platelets and the proliferation of smooth muscle. These effects of CO typically depend on the activation of soluble guanylate cyclase activity. Although toxic at elevated concentrations, exogenous CO may exert anti-inflammatory and anti-apoptotic properties at low concentration, which depend on the modulation of mitogen-activated protein kinase pathways. Manipulation of the HO-1/CO system, either by gene transfer or application of low-dose CO, could be applied in the treatment of vascular disease. Beneficial effects of HO/CO have recently been demonstrated in the limitation of ischemia/reperfusion injury during organ transplantation.