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Positive feedback-loop of telomerase reverse transcriptase and 15-lipoxygenase-2 promotes pulmonary hypertension.

AbstractOBJECTIVE:
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.
APPROACH AND 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.
AuthorsTingting Shen, Jun Ma, Lei Zhang, Xiufeng Yu, Mengmeng Liu, Yunlong Hou, Yanyan Wang, Cui Ma, Shuzhen Li, Daling Zhu
JournalPloS one (PLoS One) Vol. 8 Issue 12 Pg. e83132 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID24376652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Hydroxyeicosatetraenoic Acids
  • Monocrotaline
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • Arachidonate 15-Lipoxygenase
  • Telomerase
Topics
  • Animals
  • Anoxia (genetics, metabolism, pathology)
  • Arachidonate 15-Lipoxygenase (genetics, metabolism)
  • Blood Pressure
  • Cell Cycle (genetics)
  • Cell Proliferation
  • Cells, Cultured
  • Feedback, Physiological
  • Gene Expression Regulation
  • Humans
  • Hydroxyeicosatetraenoic Acids (metabolism)
  • Hypertension, Pulmonary (chemically induced, genetics, metabolism, pathology)
  • Male
  • Monocrotaline
  • Myocytes, Smooth Muscle (metabolism, pathology)
  • Protein Binding
  • Pulmonary Artery (metabolism, pathology)
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Telomerase (genetics, metabolism)

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