Abstract 1832: A Novel Stretch Effector Within the Cardiomyocyte Sarcomere is Critical to Sense Biomechanical Stress Responses Leading to Pathological Hypertrophy
Biomechanical stress responses have been shown to play a pivotal role in the pathological processes underlying cardiac disease. Little is known on how biomechanical stress is sensed by cardiomyocytes to transduce intracellular hypertrophic signals, which then lead to disease. However, recent studies have identified cytoskeletal proteins of the LIM domain family as candidate proteins involved in biomechanical stress responses leading to cardiac disease. We have identified and characterized a new group of LIM-only proteins with four and one half LIM domains (FHL), which are enriched in adult striated muscle. We hypothesized that FHL1 would play an essential role in stress induced hypertrophy and disease in vivo, since it is the only FHL member to be upregulated in mouse hearts subsequent in vivo pressure overload induced hypertrophy, hypertropic agonists as well as in patients exhibiting hypertrophic cardiomyopathy. To address the functional role of FHL1 in vivo, we have generated FHL1 deficient mice using a lacZ knockin strategy. Our studies demonstrate that FHL1 is part of a novel stretch effector complex within the cardiomyocyte sarcomere, which plays a pivotal role in biomechanical stresses leading to pathological hypertrophic signaling. Loss of FHL1 in cardiac muscle resulted in a blunted response to hypertrophy and beneficial response on diastolic parameters following pressure overload-induced hypertrophy induced by transverse aortic constriction. A link to G protein coupled receptor pathway was shown when FHL1 deficiency could prevent the cardiomyopathy observed in Galphaq transgenic mice. Mechanistic studies suggest that FHL1 directly links I band titin (N2B) to the Gq pathway (via Raf/MEK/ERK) within the cardiomyocyte sarcomere to modulate compliance and hypertrophic signaling responses, respectively. We propose that I band MAPK/FHL1/titin complex is a novel molecular target within the cardiomyocyte stretch machinery which serves to sense biomechanical stress and control the transition to pathological hypertrophy, thus providing a new molecular target for the treatment of cardiac diseases involving deleterious hypertrophy.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).