Homocysteine Inhibition of Endothelium-Dependent Nitric Oxide-Mediated Dilation of Porcine Retinal Arterioles via Enhanced Superoxide Production
Homocysteine Inhibition of Endothelium-Dependent Nitric Oxide-Mediated Dilation of Porcine Retinal Arterioles via Enhanced Superoxide Production
复制标题
DOI：
10.1167/iovs.12-11082
复制
发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
Yoshida, Akitoshi
中科院分区：
文献类型：
--
作者：
Omae, Tsuneaki;Nagaoka, Taiji;Yoshida, Akitoshi
目的。血浆同型半胱氨酸（一种含硫氨基酸）浓度升高是心血管疾病的新危险因素。最近的流行病学研究证实，同型半胱氨酸水平升高与眼部血管疾病有关；然而，同型半胱氨酸对眼微血管反应性的直接影响尚不清楚。我们研究了同型半胱氨酸是否影响内皮依赖性一氧化氮（NO）介导的视网膜小动脉扩张，以及氧化应激和不同的蛋白激酶信号通路是否参与同型半胱氨酸介导的效应。分离猪视网膜小动脉，插管，加压，体外无血流。用视频显微技术记录直径变化。同型半胱氨酸（1mm， 180分钟）腔内治疗对内皮依赖性NO介导的激动剂缓激肽和A23187的反应显著减弱动脉扩张，但对内皮依赖性NO供体硝普钠的反应不明显。在超氧化物清除剂4-羟基-2,2,6,6-四甲基哌啶-1-氧（TEMPOL）、烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NAD(P) H氧化酶抑制剂罗布宁、p38激酶抑制剂SB203580和过氧化物酶体增殖物激活受体- γ (ppar - γ)激动剂吡格列酮的存在下，同型半胱氨酸对缓激肽诱导的扩张的有害影响被阻止；然而，黄嘌呤氧化酶抑制剂别嘌呤醇、JNK抑制剂SP600125或吡格列酮联合ppar - γ抑制剂GW9662均无此作用。同型半胱氨酸通过从NAD(P) H氧化酶产生超氧化物抑制内皮依赖性no介导的视网膜小动脉扩张，这似乎与p38激酶有关。通过损害内皮依赖性no介导的血管反应性，同型半胱氨酸可能促进视网膜血管疾病的发展。此外，吡格列酮可能通过激活PPAR-c来预防同型半胱氨酸诱导的内皮功能障碍。（Invest Ophthalmol Vis Sci. 2013;54:2288-2295） DOI: 10.1167/iovs.12-11082
PURPOSE. Elevated plasma concentration of homocysteine, a sulfur-containing amino acid, is an emerging risk factor for cardiovascular diseases. Recent epidemiologic studies have confirmed that elevated homocysteine levels are associated with ocular vascular diseases; however, the direct effect of homocysteine on ocular microvascular reactivity remains unknown. We investigated whether homocysteine affects endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles and whether oxidative stress and distinct protein kinase signaling pathways are involved in the homocysteine-mediated effect.METHODS. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Diameter changes were recorded using videomicroscopy techniques.RESULTS. Intraluminal treatment with homocysteine (1 mM, 180 minutes) significantly attenuated arteriolar dilation in response to the endothelium-dependent NO-mediated agonists bradykinin and A23187 but not in response to the endothelium-independent NO donor sodium nitroprusside. In the presence of the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), the nicotinamide adenine dinucleotide phosphate-oxidase (NAD(P) H oxidase inhibitor apocynin, p38 kinase inhibitor SB203580, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone, the detrimental effect of homocysteine on bradykinin-induced dilation was prevented; however, neither the xanthine oxidase inhibitor allopurinol, the JNK inhibitor SP600125, or pioglitazone with PPAR-gamma inhibitor GW9662 had that effect.CONCLUSIONS. Homocysteine inhibits endothelium-dependent NO-mediated dilation in the retinal arterioles by producing superoxide from NAD(P) H oxidase, which appears to be linked with p38 kinase. By impairing endothelium-dependent NO-mediated vasoreactivity, homocysteine potentially facilitates development of retinal vascular diseases. In addition, pioglitazone can prevent homocysteine-induced endothelial dysfunction possibly by activating PPAR-c. (Invest Ophthalmol Vis Sci. 2013;54:2288-2295) DOI: 10.1167/iovs.12-11082