Journal of Clinical Investigation -- An FHL1-containing complex ...

Department of Medicine and Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Ju Chen, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. Phone: (858) 822-4276; Fax: (858) 822-1355; E-mail: juchen@ucsd.edu .

First published November 3, 2008
Received for publication November 9, 2007, and accepted in revised form September 24, 2008.

The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that four-and-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress–induced responses important for cardiac hypertrophy. Mice lacking Fhl1 displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the Gαq (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin- and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.

Cardiovascular disease and ensuing heart failure is the leading cause of human morbidity and mortality worldwide. Biomechanical stress–induced growth responses have been shown to play a pivotal role in the pathophysiology of cardiac disease and could have application for therapies. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere and transduced into intracellular signals or how dysfunction of these pathways may lead to disease. Human genetic studies and genetic mouse models have revealed a structural role for cytoskeletal proteins in the pathophysiology of cardiac disease ( ). However, the physiological relevance of these multiple interactions and functions of FHL proteins in vivo remain unclear. A growing body of evidence has suggested that FHL1 may play an important role in biomechanical stress responses involved in cardiac hypertrophy and disease. Recent studies have shown FHL1 as the only FHL member to be upregulated in mouse hearts subsequent to in vivo pressure overload induced hypertrophy and hypertrophic agonists ( ) mice. Our studies demonstrate a critical role for FHL1 to sense biomechanical stress responses important in pathological cardiac hypertrophy. Using a combination of in vitro and in vivo systems, we demonstrate interactions of FHL1 with both sarcomeric (titin N2B) and signaling (Gαq-MAPK [Gq-MAPK] cascade) components within the cardiomyocyte and demonstrate the ability of these interactions to dually affect sarcomere extensibility and hypertrophic signaling responses. Taken together, our studies demonstrate that FHL1 provides an essential connection between the muscle stretch sensor and downstream titin- and MAPK-mediated responses important in biomechanical stress responses involved in cardiac hypertrophy. These studies further shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.

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