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Abraham, D.M., Lee, T.E., Watson, L.J., Mao, L., Chandok, G., Wang, H.G., Frangakis, S., Pitt, G.S., Shah, S.H., Wolf, M.J., Rockman, H.A. (2018). The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction.  J. Clin. Invest. 128(11): 4843--4855.
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Cardiac two-pore domain potassium channels (K2P) exist in organisms from Drosophila to humans; however, their role in cardiac function is not known. We identified a K2P gene, CG8713 (sandman), in a Drosophila genetic screen and show that sandman is critical to cardiac function. Mice lacking an ortholog of sandman, TWIK-related potassium channel (TREK-1, also known Kcnk2), exhibit exaggerated pressure overload-induced concentric hypertrophy and alterations in fetal gene expression, yet retain preserved systolic and diastolic cardiac function. While cardiomyocyte-specific deletion of TREK-1 in response to in vivo pressure overload resulted in cardiac dysfunction, TREK-1 deletion in fibroblasts prevented deterioration in cardiac function. The absence of pressure overload-induced dysfunction in TREK-1-KO mice was associated with diminished cardiac fibrosis and reduced activation of JNK in cardiomyocytes and fibroblasts. These findings indicate a central role for cardiac fibroblast TREK-1 in the pathogenesis of pressure overload-induced cardiac dysfunction and serve as a conceptual basis for its inhibition as a potential therapy.

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PMC6205385 (PMC) (EuropePMC)
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    J. Clin. Invest.
    Journal of Clinical Investigation
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