Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy.
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.
Jasmin
Jean-François
JF
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pa 19107, USA.
Mercier
Isabelle
I
Dupuis
Jocelyn
J
Tanowitz
Herbert B
HB
Lisanti
Michael P
MP
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
D051242:Caveolin 1; D010446:Peptide Fragments; D016686:Monocrotaline