Retinol-binding protein 4 induces cardiomyocyte hypertrophy by activating TLR4/MyD88 pathway

Abstract

Insulin resistance plays a major role in the development and progression of cardiac hypertrophy and heart failure. Heart failure in turn promotes insulin resistance and increases the risk for diabetes.The vicious cycle determines significant mortalityinpatients with heart failureand diabetes. However, the underlying mechanisms for the vicious cycle are not fully elucidated. Here we show thatcirculatinglevelsandadiposeexpressionofretinol-bindingprotein4(RBP4),anadipokinethat contributes to systemic insulin resistance, were elevated in cardiac hypertrophy induced by transverse aortic constriction and angiotensin-II (Ang-II) infusion. Ang-II increased RBP4 expression in adipocytes, which was abolished by losartan, an Ang-II receptor blocker. The elevated RBP4 in cardiac hypertrophy may have pathophysiological consequences because RBP4 increased cell size, enhanced protein synthesis, and elevated the expression of hypertrophic markers including Anp, Bnp, and Myh7 in primary cardiomyocytes. Mechanistically, RBP4 induced the expression and activityoftoll-likereceptor4(TLR4)andmyeloiddifferentiationprimaryresponsegene88(MyD88) in cardiomyocytes, resulting in enhanced inflammation and reactive oxygen species production. Inhibitionor knockdown ofthe TLR4/MyD88 pathway attenuated inflammatory and hypertrophic responses to RBP4 stimulation. Importantly, RBP4 also reduced the expression of glucose transporter-4 and impaired insulin-stimulated glucose uptake in cardiomyocytes. This impairment was ameliorated in cardiomyocytes from TLR4 knockout mice. Therefore, RBP4 may be a critical modulatorpromoting the vicious cycleofinsulin resistanceand heart failurebyactivating TLR4/MyD88-mediated inflammatory pathways. Potentially, lowering RBP4 might break the vicious cycle and improve both insulin resistance and cardiac hypertrophy.