title: Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production.
abstract: OBJECTIVE
  To test the hypothesis that apelin protects against angiotensin II (Ang II)-induced cardiovascular fibrosis and vascular remodeling.
  
  
  RESULTS
  Wild-type mice administered apelin or apelin along with Ang II exhibited less cardiovascular fibrosis and decreased plasminogen activator inhibitor type-1 (PAI-1) gene expression than mice receiving Ang II, N-nitro-L-arginine methyl ester (L-NAME), apelin plus L-NAME or apelin plus Ang II plus L-NAME. In-vitro analysis using a luciferase construct driven by 3.1 kb of the human PAI-1 promoter revealed that apelin blocked Ang II-mediated PAI-1 gene expression. Immunoblotting for phosphorylated myosin phosphatase subunit and myosin light chain revealed that apelin blocked Ang II activation of the Rho kinase pathway, which is associated with induction of PAI-1 gene expression by Ang II. In addition, treatment of human aortic smooth muscle cells with apelin reduced PAI-1 mRNA and protein production in the presence and absence of Ang II. Conversely, L-NAME treatment attenuated the downregulation of PAI-1 by apelin in cells.
  
  
  CONCLUSIONS
  Apelin protects against cardiac fibrosis and vascular remodeling through direct regulation of PAI-1 gene expression. This protective effect is mediated through the synergistic inhibition of Ang II signaling and increased production of nitric oxide by apelin. Our data extend previous findings and provide new insight into the molecular mechanisms by which apelin elicits a cardioprotective effect.
authors.affiliation: Sanford Burnham Medical Research Institute at Lake Nona, Orlando, Florida 32827, USA.
authors.forename: Khandaker
authors.initials: K
authors.lastname: Siddiquee
authors.forename: Jessica
authors.initials: J
authors.lastname: Hampton
authors.forename: Susan
authors.initials: S
authors.lastname: Khan
authors.forename: Dan
authors.initials: D
authors.lastname: Zadory
authors.forename: Linda
authors.initials: L
authors.lastname: Gleaves
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D000818:Animals; D000073861:Apelin; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D005355:Fibrosis / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D036341:Intercellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D000804:Angiotensin II