title: Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy.
abstract: BACKGROUND
  Caveolins (Cavs), the principal structural proteins of caveolar microdomains, have been implicated in the development of pulmonary hypertension (PH). Mice with homozygous deletion of the Cav-1 gene develop PH and right ventricular hypertrophy (RVH). Reductions in pulmonary Cav-1 expression have been shown in several animal models of PH and in patients with severe PH. Whether in vivo modulation of Cav-1 expression could affect the development of PH and RVH remains unknown. Therefore, we investigated the effect of in vivo administration of a Cav-1 mimetic peptide on the development of monocrotaline (MCT)-induced PH.
  
  
  RESULTS
  Thirty minutes after injection of saline or 60 mg/kg MCT, rats were assigned to receive a daily injection of saline, a peptide corresponding to the homeodomain of the Drosophila transcription factor antennapedia (AP; 2.5 mg x kg(-1) x d(-1)), or a peptide consisting of the Cav-1-scaffolding domain coupled to AP (AP-Cav; 2.5 mg x kg(-1) x d(-1)) for 2 weeks. MCT and MCT+AP rats developed PH with respective right ventricular systolic pressures of 40.2 +/- 1.5 and 39.6 +/- 1.5 mm Hg. Administration of AP-Cav to MCT rats significantly reduced the right ventricular systolic pressure to 30.1 +/- 1.3 mm Hg. MCT and MCT+AP rats also developed pulmonary artery medial hypertrophy and RVH, which was normalized by administration of AP-Cav. Mechanistically, the development of PH was associated with reduced expression of pulmonary Cav-1 and Cav-2, hyperactivation of the STAT3 signaling cascade, and upregulation of cyclin D1 and D3 protein levels, all of which were prevented by administration of AP-Cav.
  
  
  CONCLUSIONS
  Short-term administration of a Cav-based cell-permeable peptide to MCT rats prevents the development of pulmonary artery medial hypertrophy, PH, and RVH.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pa 19107, USA.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jasmin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Dupuis
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D051242:Caveolin 1 / Q000008:administration & dosage / Q000627:therapeutic use*; D002463:Cell Membrane Permeability; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008969:Molecular Sequence Data; D016686:Monocrotaline / Q000633:toxicity*; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051242:Caveolin 1; D010446:Peptide Fragments; D016686:Monocrotaline