HuR is Activated in Cardiac Hypertrophy and Regulates β1‐AR mRNA

Abstract

Heart failure is a worldwide health burden that is often preceded by a long period of increasing hypertrophy, or enlargement, of the heart prior to the loss of cardiac function. This progression of hypertrophy is marked by a decrease in the function and expression of key proteins that regulate cardiac contractility, such as the β1‐adrenergic receptor (β1‐AR). Despite a compensatory increase in sympathetic tone, cardiac contractility and output are substantially impaired, partially through β1‐AR desensitization and decreased receptor expression via mRNA degradation. It is thought that reversing the loss of the β1‐AR mRNA may preserve cardiac function and ameliorate the progression of hypertrophy. Human Antigen‐R (HuR), a known RNA binding protein, has been shown to bind to the 3'‐untranslated region of the β1‐AR mRNA, and we hypothesized that HuR plays a role in the development of cardiac hypertrophy by regulating β1‐AR mRNA stability in cardiomyocytes.In hypertrophic hearts from mice that were subjected to chronic isoproterenol, we observed a shift in HuR subcellular localization from predominantly nuclear to increasingly cytosolic, an indication of HuR activation. Surprisingly, in hypertrophic hearts from mice that had undergone transaortic constriction (TAC), we observed that HuR activation strongly localized to regions of increased fibrosis. Futhermore, HuR translocation in hypertrophic hearts positively correlated with a near 50% decline in β1‐AR mRNA in both models of hypertrophy. Additionally, we show that in vitro knockdown of HuR by siRNA resulted in increased β1‐AR mRNA. In conclusion, these results suggest a novel role for HuR in the development of cardiac fibrosis in hypertrophy, and have demonstrated that HuR may be mediating β1‐AR mRNA degradation.