Andrew McCulloch | Alex Orailoglu | Jeffery Omens
Name: Anna Maria Raskin
Email: ajokiel @ ucsd.edu
Grad Year: 2008
LIM domain proteins have been shown to play a pivotal role in cardiomyopathy and heart failure in humans. Four and a half LIM domain protein-1 (FHL1), is a recently identified protein, which is localized along with its signaling partners (Raf/MEK/ERK) at the N2B region of the I-band in the cardiomyocyte sarcomere. This region is proposed to be responsible for titin's elastic properties and a "hotspot" for signaling molecules, and thus, believed to play a role in mechanotransduction. In vivo studies performed on FHL1 deficient mice have revealed that at baseline (ie. normal loading conditions), FHL1 deficient cardiac muscle is not phenotypically different than controls, however, with pressure overload FHL1 deficient cardiac muscle has a blunted response to hypertrophic growth. We hypothesized that FHL1 functions to stabilize titin's structure at higher loads and thus, the absence of FHL1 may increase titin's compliance at higher loads, resulting in diminished passive force transmission and hypertrophic signaling. We have developed an in vitro chamber system that facilitates stretching of adult murine cardiac papillary muscle, as a means to induce hypertrophic markers (atrial natiuretic protein (ANP)), while simultaneously measuring contractile and passive muscle properties. In wildtype RV papillary muscles, ANP expression was 3 fold greater following hypertrophic stretch, compared to unstretched controls. Unlike controls, stretched FHL1 deficient muscle has significantly lower ANP levels. Furthermore, ELK1, a downstream transcriptional target of ERK, was also significantly lower in stretched FHL1 deficient cardiac muscle compared to stretched WT tissue. Although wildtype and FHL1 deficient muscles were both shown to have similar active force properties at 20% stretch, assessment of passive properties revealed a trend where passive stress values were lower at higher loads in FHL1 deficient muscle, compared to wildtypes, suggesting increased compliance of FHL1 deficient muscle at higher loads.
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