on October 21, 2004
Published online before print October 21, 2004, doi: 10.1161/01.ATV.0000148405.18071.6a
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Submitted on February 2, 2004
Accepted on October 3, 2004
Bilirubin From Heme Oxygenase-1 Attenuates Vascular Endothelial Activation and Dysfunction
Keiichi Kawamura ;
From the First Department of Internal Medicine (K.K., K.I., H.M., Y.M.), Fukushima Medical University, the Department of Molecular Biology and Medicine (Y.W., T. Kohro, T. Kodama), University of Tokyo, and the Department of Biological Chemistry (H.I.), School of Pharmaceutical Sciences, Showa University, Japan.
* To whom correspondence should be addressed. E-mail: kishikaw{at}fmu.ac.jp.
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-
(TNF-). 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-. 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.
Key words: heme oxygenase • oxidized LDL • endothelial nitric oxide synthase • bilirubin • carbon monoxide
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