Lei Wang1, Yu-Lin Li, Cong-Cong Zhang, Wei Cui, Xia Wang, Yong Xia, Jie Du, Hui-Hua Li. 1. Department of Physiology and Pathophysiology, Beijing AnZhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China.
Abstract
AIMS: Toll-like receptor 2 (TLR2) is an important player in innate immunity, and recent studies have identified TLR2 as a critical mediator in cardiovascular diseases. Here, we investigated the involvement of TLR2 in angiotensin (Ang) II-induced cardiac fibrosis and the underlying mechanisms. METHODS AND RESULTS: TLR2 knockout (TLR2 KO) mice (B6.129-Tlr2(tm1Kir)/) or wild-type (WT) mice (C57BL/6) treated with neutralizing anti-TLR2 antibody (T2.5) were used. The expression of TLR2 mRNA and protein in the heart was significantly up-regulated on days 1, 3, and 7 after Ang II infusion (1500 ng/kg/min). Enhanced expression of TLR2 was mainly detected in macrophages and neutrophils that had infiltrated into the heart. Both knockout of TLR2 and inhibition of TLR2 by neutralizing antibody ameliorated cardiac fibrosis induced by Ang II. This improvement was associated with a reduction in the infiltration of inflammatory cells, especially macrophages, the production of inflammatory cytokines, chemokines, and the activation of nuclear factor-κB. Bone marrow transplantation experiments between WT and TLR2 KO mice revealed that Ang II-induced cardiac fibrosis is mainly mediated by bone marrow-derived inflammatory cells. Mechanically, the deficiency of TLR2 inhibits macrophage-dependent cardiac fibroblast activation through TGFβ/Smad2/3 pathway. CONCLUSION: Inhibition of TLR2 protects against Ang II-induced cardiac fibrosis by attenuating macrophage recruitment and the inflammatory response in the heart and may be a novel potential therapeutic target for hypertensive heart disease.
AIMS: Toll-like receptor 2 (TLR2) is an important player in innate immunity, and recent studies have identified TLR2 as a critical mediator in cardiovascular diseases. Here, we investigated the involvement of TLR2 in angiotensin (Ang) II-induced cardiac fibrosis and the underlying mechanisms. METHODS AND RESULTS:TLR2 knockout (TLR2 KO) mice (B6.129-Tlr2(tm1Kir)/) or wild-type (WT) mice (C57BL/6) treated with neutralizing anti-TLR2 antibody (T2.5) were used. The expression of TLR2 mRNA and protein in the heart was significantly up-regulated on days 1, 3, and 7 after Ang II infusion (1500 ng/kg/min). Enhanced expression of TLR2 was mainly detected in macrophages and neutrophils that had infiltrated into the heart. Both knockout of TLR2 and inhibition of TLR2 by neutralizing antibody ameliorated cardiac fibrosis induced by Ang II. This improvement was associated with a reduction in the infiltration of inflammatory cells, especially macrophages, the production of inflammatory cytokines, chemokines, and the activation of nuclear factor-κB. Bone marrow transplantation experiments between WT and TLR2 KO mice revealed that Ang II-induced cardiac fibrosis is mainly mediated by bone marrow-derived inflammatory cells. Mechanically, the deficiency of TLR2 inhibits macrophage-dependent cardiac fibroblast activation through TGFβ/Smad2/3 pathway. CONCLUSION: Inhibition of TLR2 protects against Ang II-induced cardiac fibrosis by attenuating macrophage recruitment and the inflammatory response in the heart and may be a novel potential therapeutic target for hypertensive heart disease.
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312