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Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity
Koichiro Kuwahara, … , Rhonda Bassel-Duby, Eric N. Olson
Koichiro Kuwahara, … , Rhonda Bassel-Duby, Eric N. Olson
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1324-1334. https://doi.org/10.1172/JCI31240.
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Research Article Cardiology

Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity

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Abstract

Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor–dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor–2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.

Authors

Koichiro Kuwahara, Gordon C. Teg Pipes, John McAnally, James A. Richardson, Joseph A. Hill, Rhonda Bassel-Duby, Eric N. Olson

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Figure 7

Heightened sensitivity of STARS-Tg mice to hypertrophic stimuli.

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Heightened sensitivity of STARS-Tg mice to hypertrophic stimuli.
(A) Wes...
(A) Western blot of STARS protein expression in tissues of α–MHC-STARS–Tg mice. Left panel shows antibody control of 293T cells transfected with or without a STARS expression vector. Lu, lung; Li, liver; Ki, kidney. (B) Heart weight/body weight (HW/BW) ratios of α–MHC-STARS–Tg mice and control wild-type littermates at 8 (n = 12) and 20 (n = 4) weeks of age. (C) Cardiac gene expression determined by RT-PCR using total RNA extracted from α–MHC-STARS–Tg mice and control wild-type littermate at 8 weeks of age (n = 6 each). *P < 0.05 versus control wild-type littermates. (D) Hearts and HW/BW ratio of α–MHC-STARS–Tg mice and wild-type littermates at 10 weeks of age with or without TAB. n = 8 (Tg) and n = 6 (WT). Original magnification, ×2. (E) BNP mRNA expression in the hearts of α–MHC-STARS–Tg mice and wild-type littermates with or without TAB (n = 3). (F) Kaplan-Meier survival curve of α–MHC-STARS–Tg and WT mice after TAB. Mice that died within 24 hours after TAB were excluded. (G) Hearts (H&E-stained) and HW/BW ratios of α–MHC-STARS–Tg mice, Cn-Tg mice, α–MHC-STARS–Tg;Cn-Tg mice, and WT mice (n = 6 in each group). Original magnification, ×2. (H) Kaplan-Meier survival curve of α–MHC-STARS–Tg mice, Cn-Tg mice, and α–MHC-STARS–Tg;Cn-Tg mice. *P < 0.05.

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