Abstract 2892: Inhibition of Toll-like Receptor-2 May Limit Cardiac Dysfunction After a Myocardial Infarction by Reducing Apoptosis via a p38 MAPK-dependent Pathway

Background: Inhibition of toll-like receptors (TLRs) may be a new treatment to prevent congestive heart failure during post-myocardial infarction (MI) surgical interventions. TLR2 knockout (KO) mice provide an opportunity to predict the effects of inhibitors and to establish the mechanisms responsible for their beneficial effects. This study was performed to establish the pathways responsible for myocardial protection in the absence of TLRs after MI. Methods and Results: In vivo study: MI was induced in TLR2 KO and wild-type (WT) C56B/6J mice by anterior coronary artery ligation. Cardiac function was preserved in the KO mice compared to the WT mice (echocardiography demonstrated higher fractional shortening and fractional area change, p<0.05) at 3, 7 and 28 days after the MI. To evaluate the mechanisms responsible for the functional improvements, cardiac cytokine production was measured. TNF-α, IL-1β and IL-6 were significantly decreased in the infarct region of KO compared to WT mice at 3 days post-MI. On day 7, IL-6 production was significantly decreased in the infarct region and TNF-α was decreased in the non-infarcted region of KO compared to WT mice. Phosphorylation of p38 MAPK was prevented, and the number of TUNEL positive nuclei was reduced in the infarct region of KO compared to WT mice. Phosphorylation of Akt was upregulated in the non-infarcted region of KO mice at 3 days after MI. There were no differences in the phosphorylation of ERK or JNK at the same time point. In vitro study: Myocardial fibroblasts were isolated from KO and WT mice, cultured, and then exposed to hydrogen peroxide. Compared to cells from WT mice, cells from KO mice exhibited greater protection (less cell death) and reduced p38 phosphorylation as early as 5 and 15 minutes after hydrogen peroxide stimulation. Conclusions: TLR2 KO mice allow the assessment of the potential benefits of TLR inhibitors. Reducing TLR2 after an infarction will decrease cytokine production and cell death in a p38 MAPK-dependent manner, which in turn will contribute to the preservation of cardiac function. Early inhibition of TLR2 function may represent a new target to prevent heart failure after MI.

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