Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody.
Citation:
Arslan F, Smeets MB, O'Neill LA, Keogh B, McGuirk P, Timmers L, Tersteeg C, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DP., Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody., Circulation., 121, 1, 2010, 80-90Download Item:
myocardial.pdf (Published (publisher's copy) - Peer Reviewed) 1.634Mb
Abstract:
Background?Reperfusion therapy for myocardial infarction is hampered by detrimental inflammatory responses partly
via Toll-like receptor (TLR) activation. Targeting TLR signaling may optimize reperfusion therapy and enhance cell
survival and heart function after myocardial infarction. Here, we evaluated the role of TLR2 as a therapeutic target using
a novel monoclonal anti-TLR2 antibody.
Method and Results?Mice underwent 30 minutes of ischemia followed by reperfusion. Compounds were administered 5
minutes before reperfusion. Cardiac function and dimensions were assessed at baseline and 28 days after infarction with
9.4-T mouse magnetic resonance imaging. Saline and IgG isotype treatment resulted in 34.5 3.3% and 31.4 2.7%
infarction, respectively. Bone marrow transplantation experiments between wild-type and TLR2-null mice revealed that
final infarct size is determined by circulating TLR2 expression. A single intravenous bolus injection of anti-TLR2
antibody reduced infarct size to 18.9 2.2% (P 0.001). Compared with saline-treated mice, anti-TLR2?treated mice
exhibited less expansive remodeling (end-diastolic volume 68.2 2.5 versus 76.8 3.5 L; P 0.046) and preserved
systolic performance (ejection fraction 51.0 2.1% versus 39.9 2.2%, P 0.009; systolic wall thickening 3.3 6.0%
versus 22.0 4.4%, P 0.038). Anti-TLR2 treatment significantly reduced neutrophil, macrophage, and T-lymphocyte
infiltration. Furthermore, tumor necrosis factor- , interleukin-1 , granulocyte macrophage colony-stimulating factor,
and interleukin-10 were significantly reduced, as were phosphorylated c-jun N-terminal kinase, phosphorylated p38
mitogen-activated protein kinase, and caspase 3/7 activity levels.
Conclusions?Circulating TLR2 expression mediates myocardial ischemia/reperfusion injury. Antagonizing TLR2 just 5
minutes before reperfusion reduces infarct size and preserves cardiac function and geometry. Anti-TLR2 therapy exerts
its action by reducing leukocyte influx, cytokine production, and proapoptotic signaling. Hence, monoclonal anti-TLR2
antibody is a potential candidate as an adjunctive for reperfusion therapy in patients with myocardial infarction. (Circulation.
2010;121:80-90.)
Sponsor
Grant Number
European Union (EU)
Author's Homepage:
http://people.tcd.ie/laoneillDescription:
PUBLISHEDPMID: 20026776
Author: O'NEILL, LUKE ANTHONY JOHN
Type of material:
Journal ArticleCollections:
Series/Report no:
Circulation.121
1
Availability:
Full text availableKeywords:
Immunology, Toll-like receptorsLicences: