title: Loss of secreted frizzled-related protein-1 leads to deterioration of cardiac function in mice and plays a role in human cardiomyopathy.
abstract: BACKGROUND
  The Wnt/β-catenin signaling pathway plays a central role during cardiac development and has been implicated in cardiac remodeling and aging. However, the role of Wnt modulators in this process is unknown. In this study, we examined the role of the Wnt signaling inhibitor secreted frizzled-related protein-1 (sFRP-1) in aged wild-type and sFRP-1-deficient mice.
  
  
  RESULTS
  sFRP-1 gene deletion mice were grossly normal with no difference in mortality but developed abnormal cardiac structure and dysfunction with progressive age. Ventricular dilation and hypertrophy in addition to deterioration of cardiac function and massive cardiac fibrosis, all features present in dilated cardiomyopathy, were observed in the aged sFRP-1 knockout mice. Loss of sFRP-1 led to increased expression of Wnt ligands (Wnt1, 3, 7b, and 16) and Wnt target genes (Wisp1 and Lef1) in aged hearts, which correlated with increased protein levels of β-catenin. Cardiac fibroblasts lacking endogenous sFRP-1 showed increased α-smooth muscle actin expression, higher cell proliferation rates, and increased collagen production consistent with the cardiac phenotype exhibited in aged sFRP-1 knockout mice. The clinical relevance of these findings was supported by the demonstration of decreased sFRP-1 gene expression and increased Wisp-1 levels in the left ventricles of patients with ischemic dilated cardiomyopathy and dilated cardiomyopathy.
  
  
  CONCLUSIONS
  This study identifies a novel role of sFRP-1 in age-related cardiac deterioration and fibrosis. Further exploration of this pathway will identify downstream molecules important in these processes and also suggest the potential use of Wnt signaling agents as therapeutic targets for age-related cardiovascular disorders in humans.
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Piotr
authors: P
authors: Sklepkiewicz
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Takayuki
authors: T
authors: Shiomi
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Rajbir
authors: R
authors: Kaur
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Jie
authors: J
authors: Sun
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Susan
authors: S
authors: Kwon
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Becky
authors: B
authors: Mercer
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Peter
authors: P
authors: Bodine
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Ralph Theo
authors: RT
authors: Schermuly
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: Isaac
authors: I
authors: George
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.).
authors: P Christian
authors: PC
authors: Schulze
authors: From the Center for Molecular Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY (P.S., T.S., R.K., J.S., S.K., B.M., J.M.D.); Women's Health Research Institute, Department of Osteoporosis, Wyeth Research, Collegeville, PA (P.B.); Max Planck Institute, Department of Pathophysiology and Pulmonary, Bad Nauheim, Germany (R.T.S.); Center for Advanced Cardiac Care, Columbia University Medical Center, New York, NY (C.S.); and Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital/Columbia University Medical Center, New York, NY (I.G.). jmd12@cumc.columbia.edu.
authors: Jeanine M
authors: JM
authors: D'Armiento
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D016922:Cellular Senescence / Q000502:physiology; D005355:Fibrosis; D020869:Gene Expression Profiling; D006439:Hemodynamics; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins
keywords: Wnt signaling pathway; cardiomyopathy, dilated; fibrosis; heart