title: Heparin reduces overcirculation-induced pulmonary artery remodeling through p38 MAPK in piglet.
abstract: BACKGROUND
  Artery remodeling is the principal change of pulmonary artery hypertension. Heparin has been shown to inhibit vascular smooth muscle cell proliferation. We hypothesized that heparin may modulate vascular remodeling in pulmonary artery hypertension, and explored the mechanism.
  
  
  METHODS
  A localized overcirculation-induced artery remodeling was created in piglets by anastomosing the left lower lobe pulmonary artery (LLLPA) to the thoracic aortic artery. Piglets were treated with heparin or saline for 4 weeks. Hemodynamic data were collected, and histology of the lung was assessed. We investigated the expressions of several candidate genes in lung and further observed the involvement of P38 mitogen-activated protein kinases (MAPK). The effects of heparin on the growth of cultured pulmonary arterial vascular smooth muscle cell and P38 MAPK expression were further determined under various conditions.
  
  
  RESULTS
  Four weeks after the shunt setup, overcirculation caused significant LLLPA remodeling, pressure increase, and pulmonary vascular resistance increase, and LLLPA flow reduction compared with that immediately after the shunt setup. Heparin reduced the LLLPA remodeling, pressure, and pulmonary vascular resistance, and increased the LLLPA flow compared with that not heparin treated. Shunt and heparin treatment did not change the piglet's systemic hemodynamics. Shunt increased the expression of P38 MAPK and heparin decreased its expression in the shunted LLLPA. Both heparin and P38 MAPK inhibitor suppressed VSMC growth and P38 MAPK expression in the cultured VSMC, but they did not present additive effects when the two treatments were combined.
  
  
  CONCLUSIONS
  Heparin reduces overcirculation-induced pulmonary artery remodeling through a P38 MAPK-dependent pathway.
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Seng
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: Beagle
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Olga
authors.initials: O
authors.lastname: Syrkina
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: chales@partners.org.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hales
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013552:Swine; D066253:Vascular Remodeling / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D006493:Heparin; D048051:p38 Mitogen-Activated Protein Kinases