Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy

Abstract

The RNA binding protein Human antigen R (HuR) interacts with specific AU-rich domains in target mRNAs and is highly expressed in many cell types, including cardiomyocytes. However, the role of HuR in cardiac physiology is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic cardiac myocytes. Specifically, HuR cytoplasmic translocation is significantly increased in NRVMs (neonatal rat ventricular myocytes) following treatment with phenylephrine or angiotensin II, agonists of two independent Gαq-coupled GPCRs known to induce hypertrophy. This Gq-mediated HuR activation is dependent on p38 MAP kinase, but not canonical Gq-PKC signaling. Furthermore, we show that HuR activation is necessary for Gq-mediated hypertrophic growth of NRVMs as siRNA-mediated knockdown of HuR inhibits hypertrophy as measured by cell size and expression of ANF (atrial natriuretic factor). Additionally, HuR overexpression is sufficient to induce hypertrophic cell growth. To decipher the downstream mechanisms by which HuR translocation promotes cardiomyocyte hypertrophy, we assessed the role of HuR in the transcriptional activity of NFAT (nuclear factor of activated T cells), the activation of which is a hallmark of cardiac hypertrophy. Using an NFAT-luciferase reporter assay, we show an acute inhibition of NFAT transcriptional activity following pharmacological inhibition of HuR. In conclusion, our results identify HuR as a novel mediator of cardiac hypertrophy downstream of the Gq-p38 MAPK pathway, and suggest modulation of NFAT activity as a potential mechanism.

17β-Estradiol attenuates p38MAPK activity but not PKCα induced by angiotensin II in the brain

“…Because PKC is not involved in AVP release induced by ANGII, it is reasonable to suggest that the activation of p38 MAPK can be PKC independent. Indeed, recent studies have reported PKC-independent p38 MAPK activation in some tissues (Lemonnier et al 2004, Samuvel et al 2005, Slone et al 2016. Moreover, we observed that E2 prevented the ANGII-induced p38 MAPK phosphorylation in the PVN and the SON, which can explain the inhibitory effect of E2 on ANGII-induced OT and AVP secretion.…”

Human antigen R as a therapeutic target in pathological cardiac hypertrophy

“…While relatively little is known about the role of HuR in the myocardium, RNA binding proteins such as HuR are becoming recognized as potentially central regulators of cardiac physiology and pathology (6,7). We have recently shown that HuR is both necessary and sufficient for hypertrophic growth in cultured primary rat myocytes in response to hypertrophic stimuli in vitro (8).…”

Celecoxib treatment improves muscle function in mdx mice and increases utrophin A expression

“…In fact, HuR was previously reported to promote translation of target mRNAs by interacting with IRES sequences located in the 59 UTR (94,95). Moreover, HuR can be activated by p38 MAPK to stabilize target mRNAs (56,(96)(97)(98) and in this context, Farooq et al (56) showed that HuR is required for the survival motor neuron protein increase seen in celecoxib-treated NT2 cells. In our work, we observed that celecoxib induced a marked ;2and 4-fold increase in HuR protein levels in TA and DIA muscles, respectively (Supplemental Fig.…”