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An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice
Farah Sheikh, … , Andrew D. McCulloch, Ju Chen
Farah Sheikh, … , Andrew D. McCulloch, Ju Chen
Published November 3, 2008
Citation Information: J Clin Invest. 2008;118(12):3870-3880. https://doi.org/10.1172/JCI34472.
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Research Article Cardiology Article has an altmetric score of 9

An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice

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Abstract

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.

Authors

Farah Sheikh, Anna Raskin, Pao-Hsien Chu, Stephan Lange, Andrea A. Domenighetti, Ming Zheng, Xingqun Liang, Tong Zhang, Toshitaka Yajima, Yusu Gu, Nancy D. Dalton, Sushil K. Mahata, Gerald W. Dorn II, Joan Heller-Brown, Kirk L. Peterson, Jeffrey H. Omens, Andrew D. McCulloch, Ju Chen

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Figure 2

FHL1 is linked to the Gq signaling pathway in cardiomyocytes.

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FHL1 is linked to the Gq signaling pathway in cardiomyocytes.
(A) Fhl1 e...
(A) Fhl1 expression in cardiomyocytes following phenylephrine (PE) and angiotensin II treatment as well as viral Gq overexpression, using a constitutively active Gq virus and Gq transgenic mouse model. Left and middle: RNA (10 μg) was electrophoresed from control and agonist-/viral-treated cardiomyocytes and analyzed using a cDNA probe spanning the Fhl1 coding region. GAPDH or 28S RNA was used as a loading control. Right: Protein (25 μg) from WT and Gq+ hearts at 12 weeks of age were subjected to SDS-PAGE and analyzed for FHL1 (~32 kDa) protein using FHL1 antibodies. GAPDH (~37 kDa) protein was used to normalize for loading. (B) LV weight/BW ratios in WT, KO, Gq+, and double KO/Gq+ mice at 12 weeks of age (n = 6). Paraffin sections from Gq+ and KO/Gq+ hearts were stained for nuclei and cytoplasm, respectively, with hematoxylin and eosin. Scale bar: 2.5 mm. (C) Anf, β-MHC, and skeletal α-actin RNA expression in WT, KO, Gq+, and KO/Gq+ LVs (n = 4) were normalized for Gapdh expression and presented as fold induction relative to WT. (D) Echocardiographic measurements obtained from WT, KO, Gq+, and KO/Gq+ LVs at 12 weeks of age. LVIDd, LV internal dimension at end-diastole. *P < 0.05; **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 7 patents
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