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Pharmacological inhibition of Human Antigen R (HuR) blunts fibroblast activation and cardiac fibrosis
Author(s) -
Green Lisa C,
Anthony Sarah R,
Slone Samuel,
Lanzillotta Lindsey,
Lorenz John,
Tranter Michael
Publication year - 2019
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.2019.33.1_supplement.817.7
Subject(s) - fibrosis , periostin , myofibroblast , fibronectin , cardiac fibrosis , ctgf , western blot , chemistry , fibroblast , extracellular matrix , microbiology and biotechnology , cancer research , medicine , biology , in vitro , growth factor , receptor , biochemistry , gene
Heart failure is one of the leading causes of death globally, and the physiology of a failing heart is often worsened by the presence of cardiac fibrosis. Cardiac fibrosis is marked by the chronic activation of fibroblasts into myofibroblasts and excessive extracellular matrix (ECM) protein deposition, leading to decreased contractility and compliance of the myocardium. In this work we show that Human Antigen R (HuR), a stabilizing RNA binding protein, plays a critical role in the activation of fibroblasts and the subsequent fibrosis. In vivo , we used the transverse aortic constriction (TAC) model of heart failure and started treatment with a small molecule inhibitor of HuR four weeks after TAC surgeries. At the end of the eleven‐week study, the mice treated with the HuR inhibitor had markedly reduced fibrosis shown by Masson's Trichrome staining. Western blot and qRT‐PCR analysis also revealed a decreased expression of fibrotic markers such as fibronectin and periostin in the hearts from mice treated with HuR inhibitor. In vitro , we also saw that pharmacologically inhibiting HuR in fibroblasts isolated from adult mouse hearts blunts the activation of fibroblasts using assays such as the scratch assay. To identify a potential underlying mechanism for direct reduction in fibrosis via HuR inhibition, we interrogated the connection between HuR and TGFβ, a well‐known driving factor in fibrotic initiation and progression. Using an Actinomycin D stability assay on isolated primary myocytes, we showed a decrease in TGFβ mRNA stability upon inhibition of HuR. We also performed RNA immunoprecipitation and the results support a direct binding of HuR to TGFβ mRNA. Taken together, these suggest HuR may play a central role in the regulating the stability of TGFβ, thereby affecting pro‐fibrotic signaling. In conclusion, these results suggest that HuR is a promising therapeutic target for the reduction of cardiac fibrosis. Support or Funding Information This work was partially funded by an AHA Scientist Development Grant (MT), NIH R01 HL132111 (MT), and T32HL125204‐4 (JM, EK) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .