title: Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability.
abstract: BACKGROUND
  L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes.
  
  
  RESULTS
  We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypo-osmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in α1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in α1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and α1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals
  
  
  CONCLUSIONS
  PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of α1C protein.
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Zully
authors.initials: Z
authors.lastname: Pedrozo
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Cyndi R
authors.initials: CR
authors.lastname: Morales
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Ariel
authors.initials: A
authors.lastname: Contreras-Ferrat
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Carolina
authors.initials: C
authors.lastname: Fernández
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT. joseph.hill@utsouthwestern.edu slavander@uchile.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.affiliation: From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT. joseph.hill@utsouthwestern.edu slavander@uchile.cl.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006332:Cardiomegaly / Q000209:etiology* / Q000517:prevention & control; D002478:Cells, Cultured; D005355:Fibrosis; D006984:Hypertrophy; D007038:Hypotonic Solutions / Q000494:pharmacology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D025941:Protein Interaction Mapping; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D050396:TRPP Cation Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D015415:Biomarkers; D020746:Calcium Channels, L-Type; D007038:Hypotonic Solutions; D011993:Recombinant Fusion Proteins; D050396:TRPP Cation Channels; C419385:L-type calcium channel alpha(1C)
keywords: cardiomegaly; mechanotransduction, cellular