Background-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 p38␣/ MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia. Methods and Results-Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol Ͼ4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (nϭ27) or placebo (nϭ29) 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 (Pϭ0.01 and Pϭ0.03) compared with responses in control subjects (nϭ12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; Pϭ0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; Pϭ0.02), and to L-NMMA by 10% (95% confidence interval, Ϫ1 to 23; Pϭ0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, Ϫ81 to Ϫ6%; PϽ0.05) in patients treated with losmapimod compared with placebo. Conclusions-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. Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT00474864. (Circulation. 2011;123:515-523.) Key Words: endothelial function Ⅲ hypercholesterolemia Ⅲ nitric oxide Ⅲ p38 MAPK Ⅲ vasodilation A therosclerosis is regarded as a complex condition in which inflammation plays a pivotal role, involving low-density lipoprotein (LDL) deposition and oxidation, recruitment of inflammatory cells, and release of cytokines and endothelial dysfunction. 1,2 Reduced nitric oxide (NO) bioavailability accompanies all stages of atherosclerosis and is associated with increased cardiovascular risk. 3
Clinical Perspective on p 523The release of NO is a complex process that can be affected by a number of physiological and pathophysiological factors, 4 including serum levels of LDL, which, when oxidized, have increased atherogenic potential. 5 Oxidized LDL reduces NO bioavailability, destabilizes endothelial NO synthase mRNA, 6 Received February 26, 2010; accepted November 19, 2010 Several p38 MAPK inhibitors are effective in a variety o...