Abstract
Four and a half LIM domain (FHL) protein family members, FHL1 and FHL2, are multifunctional proteins that are enriched in cardiac muscle. Although they both localize within the cardiomyocyte sarcomere (titin N2B), they have been shown to have important yet unique functions within the context of cardiac hypertrophy and disease. Studies in FHL1-deficient mice have primarily uncovered mitogen-activated protein kinase (MAPK) scaffolding functions for FHL1 as part of a novel biomechanical stretch sensor within the cardiomyocyte sarcomere, which acts as a positive regulator of pressure overload-mediated cardiac hypertrophy. New data have highlighted a novel role for the serine/threonine protein phosphatase (PP5) as a deactivator of the FHL1-based biomechanical stretch sensor, which has implications in not only cardiac hypertrophy but also heart failure. In contrast, studies in FHL2-deficient mice have primarily uncovered an opposing role for FHL2 as a negative regulator of adrenergic-mediated signaling and cardiac hypertrophy, further suggesting unique functions targeted by FHL proteins in the “stressed” cardiomyocyte. In this review, we provide current knowledge of the role of FHL1 and FHL2 in cardiac muscle as it relates to their actions in cardiac hypertrophy and cardiomyopathy. A specific focus will be to dissect the pathways and protein-protein interactions that underlie FHLs’ signaling role in cardiac hypertrophy as well as provide a comprehensive list of FHL mutations linked to cardiac disease, using evidence gained from genetic mouse models and human genetic studies.
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Funding
Y.L and J.Z are recipients of the American Heart Association Postdoctoral Fellowship. W.B is a recipient of the National Science Foundation graduate research fellowship. F.S. is supported by grants from NIH/NHLBI (HL09780) and Tobacco-Related Disease Research program (24RT-22).
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Yan Liang declares that she has no conflict of interest. William H. Bradford declares that he has no conflict of interest. Jing Zhang declares that she has no conflict of interest. Farah Sheikh declares that she has no conflict of interest.
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This article is part of a Special Issue on ‘Heart Failure Due to Non-Myofibrillar Defects’ edited by Elisabeth Ehler and Katja Gehmlich.
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Liang, Y., Bradford, W.H., Zhang, J. et al. Four and a half LIM domain protein signaling and cardiomyopathy. Biophys Rev 10, 1073–1085 (2018). https://doi.org/10.1007/s12551-018-0434-3
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DOI: https://doi.org/10.1007/s12551-018-0434-3