Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans.

Abstract

OBJECTIVE:

To evaluate whether a p38α/β 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 (n=46), or placebo (n=46) daily for 28 days, starting 3 days before PCI. On day 3, before PCI, hsCRP was decreased in the SB-681323 group relative to the placebo group (29% lower; P=0.02). After PCI, there was a statistically significant attenuation in the increase in hsCRP in the SB-681323 group relative to the placebo group (37% lower on day 5 [P=0.04]; and 40% lower on day 28 [P=0.003]). There were no adverse safety signals after 28 days of treatment with SB-681323.

CONCLUSIONS:

In the setting of statin therapy, SB-681323 significantly attenuated the post-PCI inflammatory response, as measured by hsCRP. This inflammatory dampening implicates p38 mitogen-activated protein kinase in the poststent response, potentially defining an avenue to limit poststent restenosis.

• Authors: Lea Sarov-Blat, John M Morgan, Pedro Fernandez, Rachel James, Zixing Fang, Mark R Hurle, Charlotte Baidoo, Robert N Willette, John J Lepore, Svend E Jensen, Dennis L Sprecher
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 11 Pg. 2256-63 (Nov 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20689074 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• C-Reactive Protein
• p38 Mitogen-Activated Protein Kinases

Topics

• Aged
• Angioplasty, Balloon, Coronary (adverse effects)
• Anti-Inflammatory Agents (therapeutic use)
• C-Reactive Protein (analysis)
• Coronary Artery Disease (therapy)
• Coronary Vessels (injuries)
• Double-Blind Method
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Inflammation (blood)
• Male
• Middle Aged
• Prosthesis Implantation (adverse effects)
• Stents (adverse effects)
• Vascular System Injuries (blood, etiology, prevention & control)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)