Abstract 117: TWEAK (Tumor Necrosis Factor-Like Weak Inducer of Apoptosis) Impedes Healing After Myocardial Infarction in Mice
Introduction: TNF-related weak inducer of apoptosis (TWEAK) triggers multiple cellular responses involved in left ventricular remodelling after myocardial infarction (MI), including cytokine production, inflammation, and wound healing. We therefore hypothesized that TWEAK-Fn14 interactions improve wound healing after experimental MI.
Methods/Results: We investigated the effects of exogenous TWEAK by applying (1) cross-linked TWEAK - activating the classical NF-kB-signalling pathway, (2) TWEAK and (3) human serum albumin-tagged (HSA)-TWEAK - both activating the alternative NFkB-signalling pathway, or (4) placebo after the induction of experimental MI. Treatment with TWEAK and HSA-TWEAK surprisingly resulted in significantly higher mortality after MI (survival, placebo vs. TWEAK vs. HSA-TWEAK, 66.7 (10 of 15) vs. 14.3 (4 of 26) vs. 7.1 % (1 of 19)) due to cardiac ruptures in the TWEAK- and HSA-TWEAK groups. Ruptures were not related to changes in cardiac architecture since left ventricular dimensions as measured by echocardiography were identical between HSA-TWEAK and the placebo group three days after MI, a time point where cardiac ruptures had not taken place yet. We rule out direct remodelling defects, since MMP9 mRNA expression and proteolytic activity (gelatine zymography), and collagen1α1 mRNA expression were not altered between the groups. HSA-TWEAK induced an exaggerated inflammatory response: Infiltration of neutrophils into the border zone was significantly increased as assessed by immunohistochemistry (placebo vs. HSA-TWEAK, 297.91 vs. 455.75 neutrophils/ mm2, p < 0.001). FACS-Analysis showed a significant up-regulation of CD45+-cells in the infarcted area (CD45+-cells, placebo vs. HSA-TWEAK, 4.52 vs. 9.38 %, p < 0.05). This was associated with the up-regulation of genes important for the recruitment (MIP2, MCP-1 and MCP-5) and differentiation (IL5, IL12 and IFN-γ) of leukocytes (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).
Conclusion: Treatment with TWEAK reduces survival after experimental MI due to left ventricular rupture. This may be mediated by an exaggerated inflammatory response.
- © 2012 by American Heart Association, Inc.