title: Identification of small proline-rich repeat protein 3 as a novel atheroprotective factor that promotes adaptive Akt signaling in vascular smooth muscle cells.
abstract: OBJECTIVE
  Atherosclerosis is the primary driver of cardiovascular disease, the leading cause of death worldwide. Identification of naturally occurring atheroprotective genes has become a major goal for the development of interventions that will limit atheroma progression and associated adverse events. To this end, we have identified small proline-rich repeat protein (SPRR3) as selectively upregulated in vascular smooth muscle cells (VSMCs) of atheroma-bearing arterial tissue versus healthy arterial tissue. In this study, we sought to determine the role of SPRR3 in atheroma pathophysiology.
  
  
  RESULTS
  We found that atheroprone apolipoprotein E-null mice lacking SPRR3 developed significantly greater atheroma burden. To determine the cellular driver(s) of this increase, we evaluated SPRR3-dependent changes in bone marrow-derived cells, endothelial cells, and VSMCs. Bone marrow transplant of SPRR3-expressing cells into SPRR3(-/-)apolipoprotein E-deficient recipients failed to rescue atheroma burden. Similarly, endothelial cells did not exhibit a response to SPRR3 loss. However, atheromas from SPRR3-deficient mice exhibited increased TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive VSMCs compared with control. Cell death in SPRR3-deficient VSMCs was significantly increased in vitro. Conversely, SPRR3-overexpressing VSMCs exhibited reduced apoptosis compared with control. We also observed a PI3K (phosphatidylinositol 3-kinase)/Akt-dependent positive association between SPRR3 expression and levels of active Akt in VSMCs. The survival advantage seen in SPRR3-overexpressing VSMCs was abrogated after the addition of a PI3K/Akt pathway inhibitor.
  
  
  CONCLUSIONS
  These results indicate that SPRR3 protects the lesion from VSMC loss by promoting survival signaling in plaque VSMCs, thereby significantly decreasing atherosclerosis progression. As the first identified atheroma-specific VSMC prosurvival factor, SPRR3 represents a potential target for lesion-specific modulation of VSMC survival.
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Segedy
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Amy L
authors.initials: AL
authors.lastname: Pyle
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Youmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Parmjit
authors.initials: P
authors.lastname: Jat
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: James B
authors.initials: JB
authors.lastname: Atkinson
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.).
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.affiliation: From the Department of Pathology, Microbiology, and Immunology (A.K.S., B.L., S.F., J.B.A., P.P.Y.) and Departments of Veterans Affairs Medical Center (J.B.A., P.P.Y.), Pharmacology (M.F.L.), and Medicine (Y.Z., V.R.B., S.F., M.F.L., P.P.Y.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London, United Kingdom (P.J.); Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH (A.L.P.); and Department of Pathology, The Ohio State University, Columbus (A.L.P.). pampee.young@vanderbilt.edu.
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D055233:Cornified Envelope Proline-Rich Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D055233:Cornified Envelope Proline-Rich Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: akt Proto-Oncogene Protein; atherosclerosis; muscle, smooth, vascular