Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Journal of Cellular and Molecular Medicine

Li Liu¹  Yin Wang²  Zhi-Yong Cao³  Meng-Meng Wang¹  Xue-Mei Liu¹  Ting Gao¹  Qi-Kuan Hu¹  Wen-Jun Yuan¹ 

[1] Department of Physiology and Key Lab of Ministry of Education in Fertility Preservation and Maintenance, Ningxia Medical University, Yinchuan, China;Department of Ultrasonography, Changhai Hospital, Shanghai, China;Department of General Internal Medicine, Branch of 411 Hospital of People's Liberation Army, Shanghai, China

关键词: heart failure;    inflammation;    toll‐like receptor;    cardiomyocyte;   

DOI  :  10.1111/jcmm.12659

来源: Wiley

【 摘 要 】

Abstract

It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll-like receptors (TLRs) that respond to pathogen- and damage-associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4-mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (B_max) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4-blocking antibodies. We conclude that the expression, ligand-binding capacity and pro-inflammatory function of cardiomyocyte TLR4 are up-regulated after long-term MI, which promote inflammation and exacerbate heart failure.

【 授权许可】

CC BY   
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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