Inhibition of p38 Mitogen-Activated Protein Kinase Reduces Inflammation After Coronary Vascular Injury in Humans

Abstract

Objective-To evaluate whether a p38␣/␤ mitogen-activated protein kinase inhibitor, SB-681323, would limit the elevation of an inflammatory marker, high-sensitivity C-reactive protein (hsCRP), after a percutaneous coronary intervention (PCI). Methods and Results-Coronary artery stents provide benefit by maintaining lumen patency but may incur vascular trauma and inflammation, leading to myocardial damage. A key mediator for such stress signaling is p38 mitogen-activated protein kinase. Patients with angiographically documented coronary artery disease receiving stable statin therapy and about to undergo PCI were randomly selected to receive SB-681323, 7.5 mg (nϭ46), or placebo (nϭ46) Key Words: angina pectoris Ⅲ atherosclerosis Ⅲ ischemia Ⅲ stent Ⅲ vascular biology Ⅲ inflammation P ercutaneous coronary intervention (PCI) has become the predominant form of coronary artery revascularization. 1 The benefits for resolution of chronic angina and/or salvation of ischemic myocardium during acute coronary syndromes are well documented. 2 However, PCI procedures can also injure the vessel wall, generating a considerable inflammatory response and smooth muscle cell proliferation, 3,4 culminating in restenosis at the lesion site (observed in 5% to 10% of subjects during the first year after PCI). 5,6

New Therapeutic Targets in Cardiology

“…The study was not powered to look at clinical end points, but there was a significant reduction in episodes of angina and major adverse cardiac events, albeit on a post hoc analysis. 108 There was no significant difference in procedure-related troponin I release between groups. The results suggest that p38 inhibition can suppress the chronic systemic inflammatory state associated with atherosclerosis, and the response associated with acute injury, as well.…”

“…SB681323 was associated with a reduction in CRP both immediately before, and after, percutaneous coronary intervention. 108 The mean reduction in CRP area under the curve over the 28 days was 40%. 108 There were also reductions in other inflammatory markers such as myeloperoxidase, interleukin-6, and interleukin-8.…”

“…108 The mean reduction in CRP area under the curve over the 28 days was 40%. 108 There were also reductions in other inflammatory markers such as myeloperoxidase, interleukin-6, and interleukin-8. The study was not powered to look at clinical end points, but there was a significant reduction in episodes of angina and major adverse cardiac events, albeit on a post hoc analysis.…”

“…The results suggest that p38 inhibition can suppress the chronic systemic inflammatory state associated with atherosclerosis, and the response associated with acute injury, as well. 108 The lack of effect on myocardial infarction is perhaps not surprising given the prerequisites for cardioprotection to manifest, including complete and timely reperfusion are absent with most periprocedural PCI-related injury. 110 Perhaps the most interesting and ambitious study is in the setting of non-ST-elevation myocardial infarction by GlaxoSmithKline (with losmapimod at 7.5 mg BID with or without a 15-mg loading dose for 12 weeks in comparison with placebo, NCT00910962).…”

Major Contribution of the P2Y 1 Receptor in Purinergic Regulation of TNFα-Induced Vascular Inflammation

“…Interestingly, treatment with the p38 MAPK inhibitor SB203580 has been shown to reduce atherosclerotic disease progression in ApoE Ϫ/Ϫ mice 36 and vascular inflammation in patients undergoing percutaneous coronary intervention. 37 Moreover, because insulin has been found to induce or potentiate TNF␣-induced VCAM-1 expression through a mechanism principally involving p38 MAPK, 38 -40 inhibiting P2Y 1 and thus, indirectly, TNF␣-induced activation of the p38 MAPK signaling pathway, might be particularly relevant in the case of hyperinsulinemia-associated diseases, such as type 2 diabetes mellitus. The search for antiinflammatory drugs that could efficiently prevent and treat atherosclerosis is very challenging, given that the existing drugs have numerous undesirable side effects.…”