Abstract 14173: Depletion of Neutrophils Ablates Cardiac Ruptures after Treatment with TWEAK (Tumor Necrosis Factor-Like Weak Inducer of Apoptosis) in a Mouse Model of Myocardial Infarction
Introduction: Many processes regulated by TNF-like weak inducer of apoptosis (TWEAK) have been implicated in the development of cardiac dysfunction, but the role of TWEAK in healing and remodelling after MI in mice is completely unknown.
Methods/Results: After left anterior descending ligation, mice were treated i.v. with human serum albumin-tagged (HSA)-TWEAK - activating the alternative NFkB-signalling pathway, or placebo. Over 8 weeks, the HSA-TWEAK treatment group had a significantly higher mortality (survival, placebo vs. HSA-TWEAK, 66.7 % (10 of 15) vs. vs. 7.1 % (1 of 19), p<0.01) due to cardiac ruptures (placebo vs. HSA-TWEAK, 7 % (1/15) vs. 58 % (11/19), p<0.01). This was not related to changes in cardiac architecture (echocardiography), extracelluar matrix remodeling (no differences in MMP9, MMP2 and collagen1α1 mRNA expression and proteolytic activity of MMPs), or increased apoptosis rates (TUNEL-staining), three days after MI, before the occurrence of ruptures. HSA-TWEAK treatment led to an excessive inflammatory response with increased infiltration of CD45+-cells into the infarcted area (FACS, placebo vs. HSA-TWEAK, 4.52 vs. 9.38 %, p < 0.05). Genes important for the recruitment and differentiation of leukocytes were significantly induced (pg/ml, placebo vs. HSA-TWEAK: p < 0.05: MIP2, 1.41 vs. 7.83; IL5, 4.13 vs. 18.75; p < 0.001: MCP-1, N.D. vs. 28.72; MCP-5, N.D. vs. 7.36; IL12, 2.07 vs. 44.51; IFN-γ, N.D. vs. 7.47). This was associated with significant higher infiltration of neutrophils into the border zone as assessed by immunohistochemistry (placebo vs. HSA-TWEAK, 297.91 vs. 455.75 neutrophils/ mm2, p < 0.001). To further study the role of neutrophils in cardiac ruptures formation, we treated infarcted mice with neutrophil-depleting antibodies (anti-Ly6G) together with HSA-TWEAK. Co-treatment resulted in significantly reduced rupture incidence in comparison to the HSA-TWEAK-group (HSA-TWEAK vs. anti-Ly6G + HSA-TWEAK: 88.9 % (8/9) vs. 28.6 % (2/7), p<0.05).
Conclusion: Treatment of mice with HSA-TWEAK upon experimental MI results in high occurrence of left ventricular ruptures. This may be mediated by an exaggerated infiltration of neutrophils and accompanying inflammation.
- © 2012 by American Heart Association, Inc.