Abstract
BackgroundSTARS (STriated muscle Activator of Rho Signaling) is a sarcomeric protein expressed early in cardiac development that acts as an acute stress sensor for pathological remodeling. However the role of STARS in cardiac development and function is incompletely understood. Here, we investigated the role of STARS in heart development and function in the zebrafish model and in vitro.Methodology and Principal FindingsExpression of zebrafish STARS (zSTARS) first occurs in the somites by the 16 somite stage [17 hours post fertilization (hpf)]. zSTARS is expressed in both chambers of the heart by 48 hpf, and also in the developing brain, jaw structures and pectoral fins. Morpholino-induced knockdown of zSTARS alters atrial and ventricular dimensions and decreases ventricular fractional shortening (measured by high-speed video microscopy), with pericardial edema and decreased or absent circulation [abnormal cardiac phenotypes in 126/164 (77%) of morpholino-injected embryos vs. 0/152 (0%) of control morpholino embryos]. Co-injection of zsrf (serum response factor) mRNA rescues the cardiac phenotype of zSTARS knockdown, resulting in improved fractional shortening and ventricular end-diastolic dimensions. Ectopic over-expression of STARS in vitro activates the STARS proximal promoter, which contains a conserved SRF site. Chromatin immunoprecipitation demonstrates that SRF binds to this site in vivo and the SRF inhibitor CCG-1423 completely blocks STARS proximal reporter activity in H9c2 cells.Conclusions/SignificanceThis study demonstrates for the first time that STARS deficiency severely disrupts cardiac development and function in vivo and revealed a novel STARS-SRF feed-forward autoregulatory loop that could play an essential role in STARS regulation and cardiac function.
Highlights
Pathological cardiac remodeling due to sustained mechanical stress, tissue injury and neurohormonal stimulus can lead to hypertrophic growth, cardiomyopathy and heart failure
Conclusions/Significance: This study demonstrates for the first time that STARS deficiency severely disrupts cardiac development and function in vivo and revealed a novel STARS-serum response factor (SRF) feed-forward autoregulatory loop that could play an essential role in STARS regulation and cardiac function
Whole mount in situ hybridization was performed in order to investigate the developmental expression pattern of zebrafish STARS (zSTARS). zSTARS expression was detected in both the atrium and ventricle of the zebrafish heart beginning at 48 hpf (Figure 1A–B). zSTARS transcript was detected in somites by the 16 somite stage (17 hpf) (Figure 1C– E)
Summary
Pathological cardiac remodeling due to sustained mechanical stress, tissue injury and neurohormonal stimulus can lead to hypertrophic growth, cardiomyopathy and heart failure. STARS (STriated muscle Activator of Rho Signaling [ known as MS1 (Myocyte Stress 1) and ABRA (Actin-Binding Rho Activating-protein)], is an evolutionarily-conserved sarcomeric actin binding protein that is acutely (and transiently) up-regulated in response to pressure overload left ventricular hypertrophy with a peak expression well before any detectable increase in left ventricular (LV) mass [1], [2]. This suggests a possible role for STARS in the initial signaling of cardiac remodeling such as the hypertrophic response. We investigated the role of STARS in heart development and function in the zebrafish model and in vitro
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