Murthy Sn, Fonseca Va, McNamara Db
Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
Exp Clin Cardiol. 2005 Fall;10(3):154-9.
The amino acid intermediate homocysteine (Hcy) is formed during the metabolism of methionine to cysteine. Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for coronary atherosclerosis. The circulating levels of total Hcy (tHcy) can increase due to intake of foods rich in methionine or deficiencies of vitamins such as folate, pyridoxine and cyanocobalamin, which are required for the metabolism of Hcy. In addition, mutations in the genes coding for Hcy metabolizing enzymes can contribute to an increase in tHcy levels. Clinical and epidemiological studies have shown that an elevated level of tHcy measured in serum or plasma is a strong predictor of cardiovascular disease risk, which appears to be greatest in patients who have HHcy following a methionine load. Intimal hyperplasia (IH) (intima/media [I/M] ratio) is the universal response of a vessel to injury and may result in vasoconstriction when left unattended. The effect of dietary HHcy on balloon catheter-injured carotid artery and its modulation (if any) by the peroxisome proliferator-activated receptor agonist gamma rosiglitazone was evaluated in 12-week-old female Sprague-Dawley rats fed either a control diet or a diet containing 1% L-methionine. Once the rats were established on the diet, the group that was fed 1% L-methionine was further subdivided and either given an aqueous preparation of 3 mg/kg/day rosiglitazone or the vehicle via oral gavage for one week. This was followed by surgically injuring the left carotid artery using a Maverick Over-The-Wire catheter (2.0 mm x 20 mm, 3.2F; Boston Scientific, USA). The rats were continued on their respective diets and drug regimen for 21 days postsurgery. On day 22 of the procedure, the rats were sacrificed for collection of blood, the carotid arteries and liver for biochemical and histological evaluation. Compared with controls there was a significant increase in both tHcy levels and I/M ratio in the rats fed 1% L-methionine (5.4+/-0.28 muM versus 32.8+/-3.01 muM, P<0.002; and 0.175+/-0.05 versus 1.05+/-0.23, P<0.005, respectively). The effect of rosiglitazone in rats fed the control diet was not prominent. On the other hand, administration of rosiglitazone to the rats on the 1% L-methionine diet significantly reduced the levels of serum tHcy (16.6+/-2.1 muM versus 32.8+/-3.01 muM, P<0.001); however, the tHcy levels remained significantly elevated compared with animals on the control diet (P<0.002). The group receiving the L-methionine diet plus rosiglitazone had an inhibition in the development of IH compared with those receiving the L-methionine diet alone (I/M of 0.278+/-0.041 versus 1.05+/-0.23, P<0.01). Moreover, the development of IH in the group receiving the L-methionine diet plus rosiglitazone treatment was not significantly different from that observed in the group on the control diet without rosiglitazone (0.278+/-0.041 versus 0.175+/-0.05, respectively). These findings may have important implications in deciphering the molecular mechanisms involved in the augmentation of IH in HHcy and modulation of this process by rosiglitazone.
氨基酸中间体同型半胱氨酸（Hcy）在蛋氨酸代谢为半胱氨酸的过程中形成。高同型半胱氨酸血症（HHcy）被认为是冠状动脉粥样硬化的独立危险因素。由于摄入富含蛋氨酸的食物或缺乏叶酸、吡哆醇和氰钴胺等Hcy代谢所需的维生素，总Hcy（tHcy）的循环水平会升高。此外，编码Hcy代谢酶的基因突变也会导致tHcy水平升高。临床和流行病学研究表明，血清或血浆中tHcy水平升高是心血管疾病风险的有力预测指标，在蛋氨酸负荷后出现HHcy的患者中风险似乎最大。内膜增生（IH）（内膜/中膜[I/M]比值）是血管对损伤的普遍反应，若不加以处理可能导致血管收缩。在12周龄雌性Sprague-Dawley大鼠中，评估了饮食性HHcy对球囊导管损伤颈动脉的影响以及过氧化物酶体增殖物激活受体激动剂γ罗格列酮对其的调节作用（若有），这些大鼠分别喂食对照饮食或含1% L-蛋氨酸的饮食。大鼠适应饮食后，喂食1% L-蛋氨酸的组进一步细分，通过口服灌胃给予3 mg/kg/天的罗格列酮水溶液或赋形剂，持续一周。随后，使用Maverick导丝导管（2.0 mm×20 mm，3.2F；美国波士顿科学公司）对左颈动脉进行手术损伤。术后21天，大鼠继续各自的饮食和药物治疗方案。在手术第22天，处死大鼠以采集血液、颈动脉和肝脏，进行生化和组织学评估。与对照组相比，喂食1% L-蛋氨酸的大鼠tHcy水平和I/M比值均显著升高（分别为5.4±0.28 μM对32.8±3.01 μM，P<0.002；以及0.175±0.05对1.05±0.23，P<0.005）。罗格列酮对喂食对照饮食的大鼠的作用不显著。另一方面，对喂食1% L-蛋氨酸饮食的大鼠给予罗格列酮可显著降低血清tHcy水平（16.6±2.1 μM对32.8±3.01 μM，P<0.001）；然而，与喂食对照饮食的动物相比，tHcy水平仍显著升高（P<0.002）。与单独接受L-蛋氨酸饮食的组相比，接受L-蛋氨酸饮食加罗格列酮的组在IH发展方面受到抑制（I/M为0.278±0.041对1.05±0.23，P<0.01）。此外，接受L-蛋氨酸饮食加罗格列酮治疗的组在IH发展方面与未接受罗格列酮的对照饮食组无显著差异（分别为0.278±0.041对0.175±0.05）。这些发现可能对解读HHcy中IH增强以及罗格列酮对该过程调节所涉及的分子机制具有重要意义。
