Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Hills Road, Cambridge, UK.
Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24.
Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen-activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38α/β MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia.
Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol >4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (n=27) or placebo (n=29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (P=0.01 and P=0.03) compared with responses in control subjects (n=12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; P=0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; P=0.02), and to L-NMMA by 10% (95% confidence interval, -1 to 23; P=0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, -81 to -6%; P<0.05) in patients treated with losmapimod compared with placebo.
Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease.
氧化型低密度脂蛋白会减少内皮细胞一氧化氮的产生（这是血管调节的重要介质），并激活 p38 丝裂原活化蛋白激酶（MAPK），这是血管炎症的介质。血管应激的动物模型先前预测，p38MAPK 抑制后血管功能会得到改善。我们假设选择性 p38α/β MAPK 抑制剂（洛马普肽；GW856553）可改善高胆固醇血症患者一氧化氮介导的血管调节受损。
未接受治疗的高胆固醇血症患者（低密度脂蛋白胆固醇>4.1mmol/L）被随机分为两组，每天两次接受洛马普肽 7.5mg（n=27）或安慰剂（n=29）治疗 28 天。排除已知有血管疾病（如糖尿病、冠心病）的患者。通过静脉闭塞容积描记法测量前臂血流量，以响应连续的动脉内输注乙酰胆碱、硝普钠和 N(G)-单甲基-L-精氨酸（L-NMMA）。与对照组（n=12）相比，乙酰胆碱和 L-NMMA 的反应明显受损（P=0.01 和 P=0.03）。在接受洛马普肽治疗的高胆固醇血症患者中，乙酰胆碱的反应提高了 25%（95%置信区间，5 至 48；P=0.01），硝普钠提高了 20%（95%置信区间，3 至 40；P=0.02），L-NMMA 提高了 10%（95%置信区间，-1 至 23；P=0.07）。与安慰剂相比，洛马普肽治疗的患者 C 反应蛋白降低了 57%（95%置信区间，-81 至-6%；P<0.05）。
洛马普肽可改善高胆固醇血症患者的一氧化氮介导的血管舒张功能，这与先前的转化动物模型的发现一致。这些数据支持这样的假设，即通过抑制 p38MAPK 活性来减轻炎症环境可改善 NO 活性。这表明 p38 MAPK 可作为心血管疾病患者的一个新靶点。
