title: Reducing endoglin activity limits calcineurin and TRPC-6 expression and improves survival in a mouse model of right ventricular pressure overload.
abstract: BACKGROUND
  Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-β1). TGF-β1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-β1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO.
  
  
  RESULTS
  We first demonstrate that endoglin is required for TGF-β1-mediated calcineurin/TRPC-6 expression and up-regulation of alpha-smooth muscle antigen (α-SMA), a marker of myofibroblast transformation, in human RV fibroblasts. Using endoglin haploinsufficient mice (Eng(+/-)) we show that reduced endoglin activity preserves RV function, limits RV fibrosis, and attenuates activation of the calcineurin/TRPC-6/α-SMA pathway in a model of angio-obliterative pulmonary hypertension. Next, using Eng(+/-) mice or a neutralizing antibody (Ab) against endoglin (N-Eng) in wild-type mice, we show that reduced endoglin activity improves survival and attenuates RV fibrosis in models of RVPO induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of RV fibrosis and calcineurin levels in wild-type mice treated with a N-Eng Ab, compared to an immunoglobulin G control.
  
  
  CONCLUSIONS
  These data establish endoglin as a regulator of TGF-β1 signaling by calcineurin and TRPC-6 in the RV and identify it as a potential therapeutic target to limit RV fibrosis and improve survival in RVPO, a common cause of death in cardiac and pulmonary disease.
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Navin K
authors.initials: NK
authors.lastname: Kapur
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Qiao
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Vikram
authors.initials: V
authors.lastname: Paruchuri
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Emily E
authors.initials: EE
authors.lastname: Mackey
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Daly
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Kishan
authors.initials: K
authors.lastname: Ughreja
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Keshan
authors.initials: K
authors.lastname: Ughreja
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Morine
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levine
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: Molecular Structure and Function Program, Hospital for Sick Children, and The Heart and Stroke Foundation Richard Lewar Center of Excellence, University of Toronto, Toronto, Ontario, Canada (M.L.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
authors.affiliation: The Molecular Cardiology Research Institute and Surgical Research Laboratories, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (N.K.K., X.Q., V.P., E.E.M., G.H.D., K.U., K.J.M., J.L., M.J.A., N.S.H., I.Z.J., R.H.K.).
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D000071063:Endoglin; D005347:Fibroblasts / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D050052:TRPC Cation Channels / Q000235:genetics* / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000199:Actins; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C508960:TGFB1 protein, human; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D053773:Transforming Growth Factor beta1; C492146:Trpc6 protein, mouse; C544013:alpha-smooth muscle actin, mouse; D019703:Calcineurin
keywords: cardiac remodeling; fibrosis; heart failure; pulmonary hypertension; right ventricle