[HTML][HTML] Human antigen R as a therapeutic target in pathological cardiac hypertrophy

LC Green, SR Anthony, S Slone, L Lanzillotta… - JCI insight, 2019 - ncbi.nlm.nih.gov
LC Green, SR Anthony, S Slone, L Lanzillotta, ML Nieman, X Wu, N Robbins, SM Jones
JCI insight, 2019ncbi.nlm.nih.gov
RNA binding proteins represent an emerging class of proteins with a role in cardiac
dysfunction. We show that activation of the RNA binding protein human antigen R (HuR) is
increased in the failing human heart. To determine the functional role of HuR in pathological
cardiac hypertrophy, we created an inducible cardiomyocyte-specific HuR-deletion mouse
and showed that HuR deletion reduces left ventricular hypertrophy, dilation, and fibrosis
while preserving cardiac function in a transverse aortic constriction (TAC) model of pressure …
Abstract
RNA binding proteins represent an emerging class of proteins with a role in cardiac dysfunction. We show that activation of the RNA binding protein human antigen R (HuR) is increased in the failing human heart. To determine the functional role of HuR in pathological cardiac hypertrophy, we created an inducible cardiomyocyte-specific HuR-deletion mouse and showed that HuR deletion reduces left ventricular hypertrophy, dilation, and fibrosis while preserving cardiac function in a transverse aortic constriction (TAC) model of pressure overload–induced hypertrophy. Assessment of HuR-dependent changes in global gene expression suggests that the mechanistic basis for this protection occurs through a reduction in fibrotic signaling, specifically through a reduction in TGF-β (Tgfb) expression. Finally, pharmacological inhibition of HuR at a clinically relevant time point following the initial development of pathological hypertrophy after TAC also yielded a significant reduction in pathological progression, as marked by a reduction in hypertrophy, dilation, and fibrosis and preserved function. In summary, this study demonstrates a functional role for HuR in the progression of pressure overload–induced cardiac hypertrophy and establishes HuR inhibition as a viable therapeutic approach for pathological cardiac hypertrophy and heart failure.
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