Human antigen R as a therapeutic target in pathological cardiac hypertrophy
Lisa C. Green, Sarah R. Anthony, Samuel Slone, Lindsey Lanzillotta, Michelle L. Nieman, Xiaoqing Wu, Nathan Robbins, Shannon M. Jones, Sudeshna Roy, A. Phillip Owens III, Jeffrey Aube, Liang Xu, John N. Lorenz, Burns C. Blaxall, Jack Rubinstein, Joshua B. Benoit, Michael Tranter
Lisa C. Green, Sarah R. Anthony, Samuel Slone, Lindsey Lanzillotta, Michelle L. Nieman, Xiaoqing Wu, Nathan Robbins, Shannon M. Jones, Sudeshna Roy, A. Phillip Owens III, Jeffrey Aube, Liang Xu, John N. Lorenz, Burns C. Blaxall, Jack Rubinstein, Joshua B. Benoit, Michael Tranter
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Research Article Cardiology Cell biology

Human antigen R as a therapeutic target in pathological cardiac hypertrophy

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.

Authors

Lisa C. Green, Sarah R. Anthony, Samuel Slone, Lindsey Lanzillotta, Michelle L. Nieman, Xiaoqing Wu, Nathan Robbins, Shannon M. Jones, Sudeshna Roy, A. Phillip Owens III, Jeffrey Aube, Liang Xu, John N. Lorenz, Burns C. Blaxall, Jack Rubinstein, Joshua B. Benoit, Michael Tranter

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Figure 7

Pharmacological inhibition of HuR following the initial onset of pathological LVH reduces progression to heart failure.

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Pharmacological inhibition of HuR following the initial onset of patholo...
(A) Kaplan Meier survival curve of mice treated with KH-3 or vehicle after randomization (randomization occurred 4 weeks after TAC surgery). (B) Whole hearts isolated 11 weeks after TAC from mice treated with vehicle or KH-3. (C) H&E stains of heart sections from mice treated with vehicle or KH-3. Scale: 3000 μm. (D) LV mass determined by weekly echocardiogram from baseline to 11 weeks after TAC (with KH-3 or vehicle treatment beginning at 4 weeks after TAC). (E) Total change in LV mass of mice treated with KH-3 or vehicle from randomization (4 weeks after TAC) to 11 weeks after TAC. (F) Ventricular weight/body weight ratio and (G) ventricular weight/tibia length of mice treated with KH-3 or vehicle 11 weeks after TAC. (H) qPCR of ANF mRNA levels from cardiac tissue of mice treated with KH-3 or vehicle 11 weeks after TAC. (I) LV diastolic volume determined by weekly echocardiogram from baseline to 11 weeks after TAC (with KH-3 or vehicle treatment beginning 4 weeks after TAC). (J) Total change in left ventricular systolic and diastolic volume of mice treated with KH-3 or vehicle from randomization (4 weeks after TAC) to 11 weeks after TAC. (K) LV ejection fraction determined by weekly echocardiogram from baseline to 11 weeks after TAC (with KH-3 or vehicle treatment beginning 4 weeks after TAC). (L) Total change in LV ejection fraction of mice treated with KH-3 or vehicle from randomization (4 weeks after TAC) to 11 weeks after TAC. (M) Positive and (N) negative ventricular contractility (dP/dt) of KH-3– and vehicle-treated mice 11 weeks after TAC. (O) Masson’s trichrome images of sectioned KH-3– and vehicle-treated hearts isolated 11 weeks after TAC. Scale bar: 100 μm. (P) Western blot of periostin and fibronectin (GAPDH loading control) in cardiac tissue isolated from mice treated with KH-3 or vehicle. Where appropriate, 2-way ANOVA and 2-tailed Student’s t tests were performed. *P <0.05, **P <0.01, and ***P <0.001 for indicated comparisons. Data shown as means ± SEM. n ≥ 5 per group.