The Toll-Like Receptor 4-Antagonist Eritoran Reduces Murine Cardiac Hypertrophy

AIMS: Toll-like receptor 4 (TLR4) recognizes lipopolysaccharides and endogenous ligands released after organ injury. Deficiency of TLR4 attenuates the development of left ventricular hypertrophy after transverse aortic constriction (TAC) in mice. We hypothesized that application of the TLR4 antagonist eritoran may also reduce cardiac hypertrophy after TAC surgery. METHODS AND RESULTS: A catheter was implanted into the jugular vein of C57BL/6 mice to allow repeated administration of eritoran (5 mg/kg body weight) or placebo. Three days after TAC or sham surgery, heart weights were determined and cardiac tissue underwent mRNA and protein quantification. The TAC placebo group exhibited a significant increase in left ventricular weight, left ventricular weight/tibia length, and left ventricular/body weight ratio compared with the sham and TAC eritoran groups. Natriuretic peptide mRNA was elevated significantly only in TAC placebo mice. Transverse aortic constriction surgery led to a distinct increase in interleukin (IL)-1β and IL-6 mRNA and protein expression in the placebo but not the eritoran group. In contrast, IL-10 was significantly increased in both eritoran groups independent from TAC. Matrix metalloproteinase zymographic activity was highest in TAC placebo animals. CONCLUSION: Application of the TLR4 antagonist eritoran attenuates the development of cardiac hypertrophy possibly by a reduction in inflammatory and increase in anti-inflammatory cytokines.