Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia

Abstract

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...

New Therapeutic Targets in Cardiology

“…p38 activity has been demonstrated to be important at various points in plaque maturation. 61 Zhao et al 62 showed that the formation of the foam cells in response to oxidized LDL depended on p38 activation. The oxidized LDL likely activates Toll-like receptors that lead to p38 activation, the degradation of extracellular matrix, and plaque instability.…”

“…For example, as measured with use of a whole blood assay, p38 activity was decreased by an average of 45% at 3 hours, and 35% at 6 hours, after the last oral dose of an inhibitor with a half-life of Ϸ12 hours. 61 Furthermore, these values were obtained after 28 days of dosing, presumably at steady state. 61 In this particular trial, the inhibitor was administered twice per day suggesting p38 activity at trough, immediately before the next dose, would be Ϸ20%.…”

“…61 Furthermore, these values were obtained after 28 days of dosing, presumably at steady state. 61 In this particular trial, the inhibitor was administered twice per day suggesting p38 activity at trough, immediately before the next dose, would be Ϸ20%. 61 Another potential advantage is the availability of more refined inhibitor scaffolds.…”

p38 Mitogen-Activated Protein Kinase Is Required for Glucosamine-Induced Endothelial Nitric Oxide Synthase Uncoupling and Plasminogen-Activator Inhibitor Expression

“…45 p38 mapk activity has also been found to be increased in endothelial progenitor cells from patients with coronary artery disease, and inhibition of p38 mapk increases the number of endothelial progenitor cells from these patients. 46 Importantly, a recent clinical study demonstrated that p38 mapk inhibitor is able to improve endothelial function in hypercholesterolemic patients, 47 and reduces atherosclerotic lesion progression in ApoE-/-mice. 48 Enhanced p38 mapk activity has also been found in adipocytes from type II diabetic patients 49 and in the heart of high-fat diet-fed rats.…”

Lentiviral-mediated p38 MAPK RNAi attenuates aldosterone-induced myocyte apoptosis

“…The p38 MAPK pathway is important in numerous cell processes, including myocyte apoptosis, hypertrophy and inflammation, which may contribute to progressive left ventricular remodeling post-MI and the transition to heart failure (14,15). Pharmacological inhibitors of p38 MAPK have been shown to decrease myocyte apoptosis and improve cardiac function and heart failure in vitro and in vivo (16,17).…”