title: Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension.
abstract: OBJECTIVE
  The G-protein-coupled receptor APJ and its ligand apelin are highly expressed in the pulmonary vasculature, but their function in this vascular bed is unclear. We hypothesized that disruption of apelin signaling would lead to worsening of the vascular remodeling associated with pulmonary hypertension (PH).
  
  
  RESULTS
  We found that apelin-null mice developed more severe PH compared with wild-type mice when exposed to chronic hypoxia. Micro-computed tomography of the pulmonary arteries demonstrated significant pruning of the microvasculature in the apelin-null mice. Apelin-null mice had a significant reduction of serum nitrate levels. This was secondary to downregulation of endothelial nitric oxide synthase (eNOS), which was associated with reduced expression of Kruppel-like factor 2 (KLF2), a known regulator of eNOS expression. In vitro knockdown studies targeting apelin in human pulmonary artery endothelial cells demonstrated decreased eNOS and KLF2 expression, as well as impaired phosphorylation of AMP-activated kinase and eNOS. Moreover, serum apelin levels of patients with PH were significantly lower than those of controls.
  
  
  CONCLUSIONS
  These data demonstrate that disruption of apelin signaling can exacerbate PH mediated by decreased activation of AMP-activated kinase and eNOS, and they identify this pathway as a potentially important therapeutic target for treatment of this refractory human disease.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Suparna M
authors.initials: SM
authors.lastname: Chandra
authors.forename: Hedi
authors.initials: H
authors.lastname: Razavi
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Rani
authors.initials: R
authors.lastname: Agrawal
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.forename: Vinicio
authors.initials: V
authors.lastname: de Jesus Perez
authors.forename: Roham T
authors.initials: RT
authors.lastname: Zamanian
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054392:Adipokines; D000328:Adult; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000097:blood / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction; D055114:X-Ray Microtomography
chemical_list: C115436:APLN protein, human; C104575:APLNR protein, human; D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D055372:AMP-Activated Protein Kinases