title: Polymerase delta-interacting protein 2 regulates collagen accumulation via activation of the Akt/mTOR pathway in vascular smooth muscle cells.
abstract: OBJECTIVE
  Polymerase delta interacting protein 2 (Poldip2) has previously been implicated in migration, proliferation and extracellular matrix (ECM) production in vascular smooth muscle cells. To better understand the role of Poldip2 in ECM regulation, we investigated the mechanism responsible for collagen I accumulation in Poldip2(+/-) mouse aortic smooth muscle cells (MASMs).
  
  
  RESULTS
  Protein degradation and protein synthesis pathways were investigated. Depletion of Poldip2 had no effect on proteasome activity, but caused a partial reduction in autophagic flux. However, the rate of collagen I degradation was increased in Poldip2(+/-) vs. Poldip2(+/+) MASMs. Conversely, activation of the PI3K/Akt/mTOR signaling pathway, involved in regulation of protein synthesis, was significantly elevated in Poldip2(+/-) MASMs as was β1-integrin expression. Suppressing mTOR signaling using Akt inhibitor or rapamycin and reducing β1-integrin expression using siRNA prevented the increase in collagen I production. While collagen I and fibronectin were increased in Poldip2(+/-) MASMs, overall protein synthesis was not different from that in Poldip2(+/)(+)MASMs, suggesting selectivity of Poldip2 for ECM proteins.
  
  
  CONCLUSIONS
  Poldip2(+/-) MASMs exhibit higher β1-integrin expression and activity of the PI3K/Akt/mTOR signaling pathway, leading to increased ECM protein synthesis. These findings have important implications for vascular diseases in which ECM accumulation plays a role.
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
authors.forename: Angélica
authors.initials: A
authors.lastname: Amanso
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
authors.forename: Thalita B
authors.initials: TB
authors.lastname: Abrahão
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lassègue
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States. Electronic address: kgriend@emory.edu.
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
mesh_terms: D000818:Animals; D001011:Aorta / Q000254:growth & development / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D024042:Collagen Type I / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism; D039641:Integrin beta Chains / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D039641:Integrin beta Chains; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C514737:mitogenin 1 protein, mouse; C546842:MTOR protein, human
keywords: Extracellular matrix; Poldip2; Vascular smooth muscle; mTOR