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Pharmacological inhibition of HuR improves survival and reduces adverse cardiac remodeling following left‐ventricular pressure overload
Author(s) -
Anthony Sarah R.,
Green Lisa C.,
Lanzillotta Lindsey,
Wu Xiaoqing,
Nieman Michelle L.,
Blaxall Burns C.,
Lorenz John N.,
Rubinstein Jack,
Xu Liang,
Tranter Michael
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.698.2
Subject(s) - pressure overload , muscle hypertrophy , heart failure , medicine , ventricular remodeling , adverse effect , ejection fraction , cardiology , left ventricular hypertrophy , myocyte , blood pressure , endocrinology , cardiac hypertrophy
Human antigen R (HuR) is a widely expressed RNA binding protein that has been implicated in numerous human diseases including cancer, neurological disorders, and cardiovascular disease. We have previously shown that HuR is both necessary and sufficient for induction of hypertrophic signaling pathways in isolated primary myocytes. In addition, data from our lab is the first to suggest that HuR expression and activation is increased in failing human hearts. To determine the role of HuR in hypertrophic signaling in vivo, we created an inducible cardiomyocyte‐specific HuR deletion mouse (iCM‐HuR −/− ), and showed that genetic deletion of HuR reduces pathology using a transverse aortic constriction (TAC) model of pressure‐overload‐induced hypertrophy, adverse cardiac remodeling, and heart failure. In this work, we sought to recapitulate this reduction in pathology using KH‐3, a novel pharmacological inhibitor of HuR, to determine the translational potential of HuR inhibition as a viable therapeutic target. Twenty wild‐type mice were randomized to either vehicle or KH‐3 at 4‐weeks post‐TAC, a time‐point consistent with substantial development of cardiac hypertrophy, and monitored via serial echocardiography for a further 7 weeks. Our results show that treatment with KH‐3 increased survival relative to vehicle controls. In addition, as compared with vehicle, KH‐3 treatment significantly abated the continued progression of left ventricular (LV) hypertrophy. This was accompanied by a significant preservation of LV ejection fraction and reduction in LV chamber dilation in KH‐3 treated mice. Importantly, KH‐3 had no effects on systemic blood pressure and no adverse reactions were observed. In conclusion, these results suggest that inhibition of HuR is a promising therapeutic approach to treat pathological LV hypertrophy. Support or Funding Information This work was partially funded by an AHA Scientist Development Grant (MT) and NIH R01 HL132111 (MT). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .