Pressure and volume overload in the heart causes mechanical stress in cardiac tissue, which in turn leads to altered phenotypes of cardiac myocytes. Mechanosensitive proteins such as integrins are thought to be the link between mechanical stress and altered phenotype. Many studies have looked at how external forces applied to cardiac myocytes influence integrin signaling; however, little is known about how changes in the internal contractile forces generated by sarcomeres affect integrin signaling. Our long term goal is to determine how changes in contractile forces influence cardiac hypertrophy. Our general hypothesis that the forces generated by contractile proteins in cardiac myocytes activate integrin mediated signal transduction leading to the remodeling seen in cardiac hypertrophy independent of neurohumoral mediated signals or externally generated stretch. In this proposal, we will alter actin-myosin mechanics using small molecule inhibitors of contractility to determine their effects on i) cardiac myocyte mechanics; ii) mechanotransduction in cardiac myocytes; and iii) cardiac myocyte hypertrophy. These studies will provide important insights into how actin-myosin mechanics influence cardiac myocyte signaling and hypertrophy and will help to establish new techniques for studying the molecular basis for the pathogenesis of cardiomyopathies. PUBLIC HEALTH RELEVANCE: In 2010 it is estimated that 81 million Americans have cardiovascular disease and heart disease is a factor in 56% of all deaths. The heart failure often involves enlargement of the heart, which is triggered by mechanical forces; however, little is known about how forces generated by the heart influence its growth. In this proposal, we will use novel approaches to study how cardiac muscle contraction influences signaling pathways associated with heart failure.
NIH ExPorter
NIH ExPorter