Fibroblast-Specific Depletion of Human Antigen R Alleviates Myocardial Fibrosis Induced by Cardiac Stress

[Display omitted] •HuR, an RNA-binding protein, plays a critical role in organ fibrosis across various pathologies.•A novel conditional tamoxifen-inducible HuR knockout mouse enabled the deletion of HuR from activated fibroblasts after cardiac injury.•Myofibroblast-specific deletion of HuR significantly limited cardiac fibrosis and preserved cardiac function in pressure overload injury.•HuR promotes myofibroblast proliferation by regulating the messenger RNA expression and stability of cyclins D1 and A2, and deletion of HuR reduced the proliferation of activated fibroblasts. Cardiac fibrosis can be mitigated by limiting fibroblast-to-myofibroblast differentiation and proliferation. Human antigen R (HuR) modulates messenger RNA stability and expression of multiple genes. However, the direct role of cardiac myofibroblast HuR is unknown. Myofibroblast-specific deletion of HuR limited cardiac fibrosis and preserved cardiac functions in pressure overload injury. Knockdown of HuR in transforming growth factor-β1–treated cardiac fibroblasts suppressed myofibroblast differentiation and proliferation. HuR deletion abrogated the expression and messenger RNA stability of cyclins D1 and A2, suggesting a potential mechanism by which HuR promotes myofibroblast proliferation. Overall, these data suggest that inhibition of HuR could be a potential therapeutic approach to limit cardiac fibrosis.