title: Positive feedback-loop of telomerase reverse transcriptase and 15-lipoxygenase-2 promotes pulmonary hypertension.
abstract: OBJECTIVE
  Pulmonary hypertension (PH) is characterized with pulmonary vasoconstriction and vascular remodeling mediated by 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) according to our previous studies. Meanwhile, telomerase reverse transcriptase (TERT) activity is highly correlated with vascular injury and remodeling, suggesting that TERT may be an essential determinant in the development of PH. The aim of this study was to determine the contribution and molecular mechanisms of TERT in the pathogenesis of PH.
  
  
  RESULTS
  We measured the right ventricular systolic pressure (RVSP) and ventricular weight, analyzed morphometric change of the pulmonary vessels in the hypoxia or monocrotaline treated rats. Bromodeoxyuridine incorporation, transwell assay and flow cytometry in pulmonary smooth muscle cells were performed to investigate the roles and relationship of TERT and 15-LO/15-HETE in PH. We revealed that the expression of TERT was increased in pulmonary vasculature of patients with PH and in the monocrotaline or hypoxia rat model of PH. The up-regulation of TERT was associated with experimental elevated RVSP and pulmonary vascular remodeling. Coimmunoprecipitation experiments identified TERT as a novel interacting partner of 15-LO-2. TERT and 15-LO-2 augmented protein expression of each other. In addition, the proliferation, migration and cell-cycle transition from G0/G1 phase to S phase induced by hypoxia were inhibited by TERT knockdown, which were rescued by 15-HETE addition.
  
  
  CONCLUSIONS
  These results demonstrate that TERT regulates pulmonary vascular remodeling. TERT and 15-LO-2 form a positive feedback loop and together promote proliferation and migration of pulmonary artery smooth muscle cells, creating a self-amplifying circuit which propels pulmonary hypertension.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Ma
authors.affiliation: Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, Heilongjiang Province, China ; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D016686:Monocrotaline; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase; D019098:Telomerase