Up‐regulated TLR 4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

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 ( TLR s) that respond to pathogen‐ and damage‐associated molecular patterns ( PAMP and DAMP ). Previous studies observed TLR 4‐mediated inflammation within days of myocardial infarction ( MI ). This study examined TLR 4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR 4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR 4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus sh RNA against TLR 4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo . Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR 4 mRNA and proteins were detected. More robust binding of TLR 4 with lipopolysaccharide ( LPS ), a PAMP ligand for TLR 4, and heat shock protein 60 ( HSP 60), a DAMP ligand for TLR 4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (B max ) of TLR 4 was increased for LPS and HSP 60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP 60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR 4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR 4 are up‐regulated after long‐term MI , which promote inflammation and exacerbate heart failure.