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Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho-kinase-dependent pathway

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Abstract

Leptin has been implicated as a key upstream mediator of pathways associated with coronary vascular dysfunction and disease. The purpose of this investigation was to test the hypothesis that leptin modifies the coronary artery proteome and promotes increases in coronary smooth muscle contraction and proliferation via influences on Rho kinase signaling. Global proteomic assessment of coronary arteries from lean swine cultured with obese concentrations of leptin (30 ng/mL) for 3 days revealed significant alterations in the coronary artery proteome (68 proteins) and identified an association between leptin treatment and calcium signaling/contraction (four proteins) and cellular growth and proliferation (35 proteins). Isometric tension studies demonstrated that both acute (30 min) and chronic (3 days, serum-free media) exposure to obese concentrations of leptin potentiated depolarization-induced contraction of coronary arteries. Inhibition of Rho kinase significantly reduced leptin-mediated increases in coronary artery contractions. The effects of leptin on the functional expression of Rho kinase were time-dependent, as acute treatment increased Rho kinase activity while chronic (3 day) exposure was associated with increases in Rho kinase protein abundance. Proliferation assays following chronic leptin administration (8 day, serum-containing media) demonstrated that leptin augmented coronary vascular smooth muscle proliferation and increased Rho kinase activity. Inhibition of Rho kinase significantly reduced these effects of leptin. Taken together, these findings demonstrate that leptin promotes increases in coronary vasoconstriction and smooth muscle proliferation and indicate that these phenotypic effects are associated with alterations in the coronary artery proteome and dynamic effects on the Rho kinase pathway.

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Acknowledgments

This publication was made possible in part by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative (CECARE); HL117620 (Tune-Mather); TL1 TR001107 and UL1 TR001108 (Noblet, Sassoon). Ingenuity Pathway Analyses were made possible by a collaboration with WV-INBRE (supported by NIH Grant P20GM103434). The authors also thank Arpad Somogyi and the Proteomics Core at The Ohio State University for performing mass spectrometry.

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  1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA

    Jillian N. Noblet, Adam G. Goodwill, Daniel J. Sassoon, Alexander M. Kiel & Johnathan D. Tune

  2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA

    Alexander M. Kiel

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Noblet, J.N., Goodwill, A.G., Sassoon, D.J. et al. Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho-kinase-dependent pathway. Basic Res Cardiol 111, 25 (2016). https://doi.org/10.1007/s00395-016-0545-6

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