Yamamoto Yasutaka, Ogino Kazuhide, Igawa Go, Matsuura Takashi, Kaetsu Yasuhiro, Sugihara Shinobu, Matsubara Koichi, Miake Junichiro, Hamada Toshihiro, Yoshida Akio, Igawa Osamu, Yamamoto Tetsuya, Shigemasa Chiaki, Hisatome Ichiro
Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan.
Hypertens Res. 2006 Nov;29(11):915-21. doi: 10.1291/hypres.29.915.
Uric acid and oxidative stress promote cardiovascular diseases, including atherosclerosis and hypertension. Xanthine oxidase, through which uric acid is generated, is a free-radical generating enzyme. The aim of the current study was to investigate whether allopurinol, an inhibitor of xanthine oxidase activity, affects vascular remodeling and vascular smooth muscle cell (VSMC) proliferation. In the carotid artery ligation model using spontaneously hypertensive rats (SHR), treatment with allopurinol induced a reduction in the neointima/media ratio by 27% (38.5+/-34.3% in the control group and 28.1 20.8% in the allopurinol-treated group, respectively, p<0.01) without alterations in vascular circumference at 3 weeks after ligation when compared to the control. Allopurinol lowered the serum uric acid concentration (147.0+/-3.6 micromol/l in the control group and 16.1+/-3.6 micromol/l in the allopurinol-treated group, respectively p<0.01) and xanthine oxidase activity, but not the blood pressure. In an in vitro study, high concentrations of uric acid (100 and 200 micromol/l) stimulated VSMC growth, but there was no stimulation of these cells by a low concentration of uric acid (50 micromol/I) or by any of three concentrations of xanthine (50, 100 and 200 micromol/l). In addition, allopurinol (5 micromol/I) had no effect on the cell growth. In conclusion, uric acid is a potent stimulator of VSMC proliferation, and allopurinol prevented vascular remodeling in SHR at least in part by inhibiting uric acid concentration.
尿酸和氧化应激会促进心血管疾病，包括动脉粥样硬化和高血压。黄嘌呤氧化酶是一种产生自由基的酶，尿酸通过它生成。本研究的目的是调查黄嘌呤氧化酶活性抑制剂别嘌呤醇是否会影响血管重塑和血管平滑肌细胞（VSMC）增殖。在使用自发性高血压大鼠（SHR）的颈动脉结扎模型中，与对照组相比，别嘌呤醇治疗使结扎后3周时的新生内膜/中膜比值降低了27%（对照组为38.5±34.3%，别嘌呤醇治疗组为28.1±20.8%，p<0.01），而血管周长没有改变。别嘌呤醇降低了血清尿酸浓度（对照组为147.0±3.6微摩尔/升，别嘌呤醇治疗组为16.1±3.6微摩尔/升，p<0.01）和黄嘌呤氧化酶活性，但没有降低血压。在一项体外研究中，高浓度尿酸（100和200微摩尔/升）刺激VSMC生长，但低浓度尿酸（50微摩尔/升）或三种浓度的黄嘌呤（50、100和200微摩尔/升）均未刺激这些细胞。此外，别嘌呤醇（5微摩尔/升）对细胞生长没有影响。总之，尿酸是VSMC增殖的有效刺激物，别嘌呤醇至少部分通过抑制尿酸浓度预防了SHR的血管重塑。
