Cardiomyocyte mechanotransduction through the integrin complex

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Mechanotransduction is the process by which cells sense external forces and respond with biological activity. In the myocardium, the cardiac myocytes are thought to sense and transmit forces both in and out of the cell through the integrin complex at the cellular membrane. This research will investigate the role of the membrane integrins and integrin-associated structural proteins within the cytoskeleton in force transmission. When these mechanical pathways are disrupted, cardiac dilation, diastolic dysfunction and heart failure can occur. There are there are two main pathways by which defects in the integrin complex results in dysfunction of the ventricle: first, the direct mechanical linkage between the extracellular matrix and the internal cytoskeleton can be defective, resulting in altered force transmission and hence diastolic dysfunction, and second, a defect in mechanosensing, from the outside in, will alter the hypertrophic and remodeling responses of the myocytes. We will investigate the significance of the integrin complex using mouse models with defective integrin and integrin-related proteins (vinculin and PINCH), which are thought to be critical components of stress sensing and force transmission at the cell membrane. The hypotheses that will be tested are (1) elastic recoil and diastolic relaxation of the left ventricle are modulated directly through mechanical linkages at the integrin complex;(2) Force transmission and mechanotransduction through the integrin complex are direction-dependent;(3) Function of the intracellular components of the integrin protein determines its mechanotransduction properties. To test these hypotheses, myocardial cells and tissues are used with state of the art experimental techniques, including magnetic resonance imaging, atomic force microscopy and isolated tissue testing, as well as cell- based functional assays. By understanding function of the proteins linked to mechanotransduction, we will advance our knowledge of the pathogenesis of cardiac hypertrophy, cardiomyopathy, the transition to heart failure and importantly, diastolic function of the myocardium. PUBLIC HEALTH RELEVANCE: This research examines the significance of forces transmitted into and out of cardiac myocytes, which play a significant role in remodeling responses of the heart tissue to overloads such as hypertension. Mouse models with defects in proteins responsible for mechanical force transmission will enable us to determine their role and how they can possibly be modified to prevent abnormal cellular and tissue responses leading the cardiac dilation and heart failure.