Abstract 17796: Toll-like Receptor 9 Signaling Pathway Ameliorates Cardiac Rupture After Myocardial Infarction by Promoting the Proliferation of Myofibroblasts

Abstract

Background: Toll-like receptor (TLR) 9 signaling pathway plays an important role in inflammatory responses in failing hearts in response to pressure overload and in the pathogenesis of heart failure. However, the role of the signaling pathway in left ventricular (LV) remodeling after myocardial infarction, where necrotic cardiomyocyte death is prominent, has not been elucidated. Methods and Results: Wild-type (WT) (n=9) and TLR9 knockout (KO) mice (n=11) were subjected to the left coronary artery ligation to induce myocardial infarction (MI). The survival ratio 7 days after MI was significantly reduced in KO mice (36.4%) than in WT mice (88.9%) (p<0.05). All of dead mice in both groups exhibited cardiac rupture. The peak time occurring rupture was 4 days after MI. The ischemia area at risk, identified by a lack of Evans blue staining were not significantly different between the WT and KO hearts (29.7% and 28.9%). Cardiovascular MRI imaging perfomed at 3 days post MI showed no difference in infarct size, LV volume and ejection fraction between WT and KO mice. The mRNA expression levels of inflammatory cytokines including IL-6 and TNFα were not significantly different in KO mice compared with WT mice. Immunohistochemical analysis did not show the significant difference in the extent of neutrophilic infiltration (CD45 positive cells) and macrophage accumulation (CD68 positive cells) in the infarct region between WT and KO mice. The number of myofibroblasts (αsmooth muscle action-positive cells), one of the cellular components in the formation of granulation tissue, was significantly reduced in KO mice (346 cells /mm2) compared to WT mice (1547 cells /mm2) (p<0.05). The number of myofibroblasts exhibiting Ki-67 immunoreactivity was also markedly lower in KO mice (113 cells /mm2) than in WT mice (789 cells /mm2) (p<0.05), indicating that the proliferative activity of myofibroblasts was significantly decreased in the infarcted regions of KO hearts. Conclusions: TLR9 signaling pathway is not involved in inflammatory responses in the infarcted regions of MI hearts but ameliorates cardiac rupture after MI by promoting the proliferation of myofibroblasts.