Leukocytic Toll-Like Receptor 2 Deficiency Preserves Cardiac Function And Reduces Fibrosis In Sustained Pressure Overload

Jiong-Wei Wang,Ya-Nan Zhang,Elise L Kessler,Carolyn S P Lam,Saskia C A De Jager,Fatih Arslan,Judith J De Haan,Toon A B Van Veen,Leo Timmers,Suet Yen Chong,Dominique P V De Kleijn,Magda S C Fontes,Xiaoyuan Wang

doi:10.1038/s41598-017-09451-3

Abstract

An involement of Toll-like receptor 2 (TLR2) has been established in cardiac dysfunction after acute myocardial infarction; however, its role in chronic pressure overload is unclear. We sought to evaluate the role of TLR2 in cardiac hypertrophy, fibrosis and dysfunction in sustained pressure overload. We induced pressure overload via transverse aortic constriction (TAC) in TLR2−/− and wild type (WT) mice, and followed temporal changes over 8 weeks. Despite similar increases in heart weight, left ventricular (LV) ejection fraction (EF) and diastolic function (mitral E/A ratio) were preserved in TLR2−/− mice but impaired in WT mice following TAC. TAC produced less LV fibrosis in TLR2−/− mice associated with lower mRNA levels of collagen genes (Col1a1 and Col3a1) and lower protein level of TGFbeta1, compared to WT mice. Following TAC, the influx of macrophages and CD3 T cells into LV was similar between TLR2−/− and WT mice, whereas levels of cyto/chemokines were lower in the heart and plasma in TLR2−/− mice. TLR2−/− bone marrow-derived cells protected against LVEF decline and fibrosis following TAC. Our findings show that leukocytic TLR2 deficiency protects against LV dysfunction and fibrosis probably via a reduction in inflammatory signaling in sustained pressure overload.

Highlights

Determined infarct size after ischemia/reperfusion injury and subsequent adverse left ventricular (LV) remodeling[7, 8]
Sustained pressure overload was induced by transverse aortic constriction (TAC) with less than 10% mortality in both wild type (WT) and Toll-like receptor 2 (TLR2)−/− mice during 8 weeks follow-up
LV ejection fraction (LVEF) was significantly lower in WT mice compared to TLR2−/− mice during 8 weeks follow-up after TAC

Summary

Introduction

Determined infarct size after ischemia/reperfusion injury and subsequent adverse LV remodeling[7, 8]. Renal ischemia-induced LV hypertrophy was reduced in TLR2−/− mice at 15 days after reperfusion, with a reduced systemic proinflammatory response[9]. We determined the temporal changes to identify the role of TLR2 in the development of LV hypertrophy, systolic/diastolic dysfunction, fibrosis and inflammation over time. We showed that TLR2 deficiency resulted in preservation of LV systolic/diastolic function and less LV fibrosis related to lower collagen formation and less cytokine/chemokine production in the TLR2−/− heart. These changes were mediated by leukocytic TLR2, and not cardiac TLR2, in response to sustained pressure overload

Methods

Results

Conclusion