Protective roles of endogenous-carbon monoxide in neointimal development elicited by arterial injury

We reported that carbon monoxide (CO) generated through heme oxygenase (HO) inhibits mitogen-induced proliferation of vascular smooth muscle cells (VS MCs). We report that balloon injury induces HO-1, the stress-inducible isoz yme of HO, in VSMCs and inhibits neointimal formation through the action of endogenous CO. Northern blot analysis and immunohistochemistry revealed th at HO-1 is markedly induced in the media as early as 1 day after injury, wh ereas only a little expression was detected in the intact carotid artery. T he neointimal proliferative changes were augmented or inhibited by the HO i nhibitors or inducer, respectively, and effects of these interventions were not altered by suppression of endogenous nitric oxide (NO), if any. To elu cidate the mechanisms by which HO controls the proliferative changes, effec ts of alterations in the HO reaction were examined by determining angiotens in II-elicited VSMC proliferation in vitro: the HO inducer attenuated and i ts inhibitor restored the proliferative response to angiotensin II(1 nM and 100 nM). Hemoglobin, a reagent trapping both NO and CO, but not methemoglo bin, which can capture NO but not CO, augmented the proliferative response. These data suggest that endogenous CO serves as a protective factor that l imits the excessive VSMC proliferation associated with vascular diseases.