title: Leptin deficiency recapitulates the histological features of pulmonary arterial hypertension in mice.
abstract: Leptin is a neuroendocrine peptide released by adipose tissue that enhances metabolism and acts on the hypothalamus to suppress appetite. Leptin also regulates aspects of cardiovascular function and low serum leptin has been associated with increased mortality in humans. We hypothesized that leptin deficiency alters the structure and function of the pulmonary vasculature.
  
  
  METHODS
  We examined two groups of C57BL/6 male mice aged 12 weeks: five ob/ob (B6.VLepob/ob) leptin-deficient and five wild type (WT) (C57BL/6) control mice. As expected, weight was significantly greater in ob/ob mice relative to WT mice [weight (g), Mean±SD): ob/ob 52±2.5 g, wild type 30±2.5 g; p<0.001]. The pulmonary vasculature of ob/ob mice and WT control animals was examined by histology, immunohistochemistry and immunofluorescence staining.
  
  
  RESULTS
  Pulmonary arterial wall thickness was significantly increased in ob/ob mice relative to WT littermates [median (interquartile range) distance in pixels: ob/ob 0.13 (0.05-0.18), wild type 0.03 (0.02-0.04); p=0.001]. The ob/ob mice also exhibited significant right ventricular hypertrophy in comparison to control animals [RV thickness (Mean±SD): ob/ob 0.75±0.19, wild type; 0.58±0.13 p<0.001]. We observed substantial macrophage infiltration and abundant proliferation of myofibroblasts and fibroblasts in histological sections of pulmonary arterioles of ob/ob mice. In addition, we noted increased hyaluronan deposition, colocalizing with SMC-actin in the pulmonary vasculature of ob/ob mice relative to WT controls.
  
  
  CONCLUSIONS
  The pulmonary pathology of leptin deficiency in ob/ob mice recapitulates many of the histological features of pulmonary vascular diseases, including pulmonary hypertension, suggesting that leptin deficiency is associated to the pathogenesis of pulmonary vascular disease.
authors: Department of Medical Biology, Faculty of Medicine, Erciyes University Melikgazi 38039, Kayseri, Turkey ; Department of Pathobiology, Lerner Research Institute, Respiratory Institute Cleveland Clinic Cleveland, Ohio, USA.
authors: Metin
authors: M
authors: Aytekin
authors: Department of Pulmonary and Critical Care Medicine, Respiratory Institute Cleveland Clinic Cleveland, Ohio, USA.
authors: Adriano R
authors: AR
authors: Tonelli
authors: Department of Pathology, Respiratory Institute Cleveland Clinic Cleveland, Ohio, USA.
authors: Carol F
authors: CF
authors: Farver
authors: Department of Pediatric Gastroenterology and Nutrition, University of California San Diego San Diego, California, USA.
authors: Ariel E
authors: AE
authors: Feldstein
authors: Department of Pathobiology, Lerner Research Institute, Respiratory Institute Cleveland Clinic Cleveland, Ohio, USA ; Department of Pulmonary and Critical Care Medicine, Respiratory Institute Cleveland Clinic Cleveland, Ohio, USA.
authors: Raed A
authors: RA
authors: Dweik
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006820:Hyaluronic Acid / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D066253:Vascular Remodeling
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D020738:Leptin; D006820:Hyaluronic Acid
keywords: Leptin; obesity; pulmonary hypertension; vasculature