Bilirubin From Heme Oxygenase-1 Attenuates Vascular Endothelial Activation and Dysfunction

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Abstract
Objective— Heme oxygenase-1 (HO-1), the rate-limiting enzyme of heme degradation, has recently been considered to have protective roles against various pathophysiological conditions. Since we demonstrated that HO-1 overexpression inhibits atherosclerotic formation in animal models, we examined the effect of HO modulation on proinflammatory cytokine production, endothelial NO synthase (eNOS) expression, and endothelium-dependent vascular relaxation responses. Methods and Results— After HO-1 induction by heme arginate (HA), vascular endothelial cell cultures were exposed to oxidized low-density lipoprotein (oxLDL) or tumor necrosis factor-α (TNF-α). HA pretreatment significantly attenuated the production of vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and macrophage colony-stimulating factor, suggesting that HO-1 induction attenuates proinflammatory responses. In addition, HO-1 overexpression also alleviated endothelial dysfunction as judged by restoration of attenuated eNOS expression after exposure to oxLDL and TNF-α. Importantly, impaired endothelium-dependent vascular relaxation responses in thoracic aortic rings from high-fat-fed LDL receptor knockout mice were also improved. These effects were observed by treatment with bilirubin not by carbon monoxide. Conclusions— These results suggest that the antiatherogenic properties of HO-1 may be mediated predominantly through the action of bilirubin by inhibition of vascular endothelial activation and dysfunction in response to proinflammatory stresses.