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

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 2

Mutational analysis of the STARS promoter.

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Mutational analysis of the STARS promoter. (A) Fragments...
(A) Fragments of the STARS upstream region linked to the hsp68 minimal promoter and lacZ were used to generate Tg mice. (B) LacZ staining of Tg mice at E12.5 carrying the indicated STARS-lacZ transgenes. H&E-stained sections of the heart are shown. (C) LacZ staining of striated muscle of Tg mice carrying STARS-lacZ construct 1. TA, tibialis anterior; EDL, extensor digitorum longis; sol, soleus. (D and E) Luciferase activity was measured in cardiomyocytes (D and E) and COS-1 cells (E) transfected with the luciferase reporter plasmid pGL3 linked to upstream fragments of the STARS gene. (F) Sequences of the M1 and M2 regions with mutations shown in red. (G) Luciferase activity was measured in cardiomyocytes transfected with –1581- or –164STARS-luc without or with mutations in the M1 and/or M2 region (mutM1, mutM2, mutM1+M2). *P < 0.05 versus reporter without mutation. (H) LacZ staining of E12.5 Tg embryos carrying wild type construct 1 or construct 1 with mutations in the M1 and M2 regions (mutM1+M2). Original magnification, ×2 (B, upper panels, and H); ×10 (B, lower panels).