TY - JOUR
T1 - Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide-Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia
AU - Cheriyan, Joseph
AU - Webb, Andrew J.
AU - Sarov-Blat, Lea
AU - Elkhawad, Maysoon
AU - Wallace, Sharon M. L.
AU - Maeki-Petaejae, Kaisa M.
AU - Collier, David J.
AU - Morgan, John
AU - Fang, Zixing
AU - Willette, Robert N.
AU - Lepore, John J.
AU - Cockcroft, John R.
AU - Sprecher, Dennis L.
AU - Wilkinson, Ian B.
PY - 2011/2/8
Y1 - 2011/2/8
N2 - 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 alpha/beta 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 >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 NG-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
AB - 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 alpha/beta 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 >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 NG-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
U2 - 10.1161/CIRCULATIONAHA.110.971986
DO - 10.1161/CIRCULATIONAHA.110.971986
M3 - Article
SN - 1524-4539
VL - 123
SP - 515
EP - 523
JO - Circulation (Baltimore)
JF - Circulation (Baltimore)
IS - 5
ER -
