Abstract 526: Short Term Administration of a Cell Permeable Caveolin-1 Peptide Prevents the Development of Pulmonary Hypertension and Right Ventricular Hypertrophy
Introduction: Caveolins (Cav), the principal structural proteins of the caveolar microdomain, 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 of pulmonary Cav-1 expression have been shown in several animal models of PH, as well as in patients with severe PH. Whether in vivo modulation of Cav-1 expression could affect the development of PH and RVH still 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.
Methods and Results: Thirty minutes after injection of saline or 60 mg/kg MCT, rats were assigned to receive a daily injection of either saline, a peptide corresponding to the homeodomain of the Drosophila transcription factor antennapedia (AP, 2.5 mg/kg/d) or a peptide consisting of the Cav-1 scaffolding domain coupled to AP (AP-Cav, 2.5 mg/kg/d) for two weeks. MCT and MCT+AP rats developed PH with respective RV systolic pressures (RVSP) of 40.2 ± 1.5 mmHg and 39.6 ± 1.5 mmHg. Daily administration of AP-Cav to MCT rats significantly reduced the RVSP to 30.1 ± 1.3 mmHg. MCT and MCT+AP rats also developed pulmonary artery medial hypertrophy and RVH, which were normalized by daily administration of AP-Cav. Mechanistically, the development of PH was associated with reduced expression of pulmonary Cav-1 and Cav-2, hyper-activation of the STAT3 signaling cascade and upregulation of cyclin D1 and D3 protein levels, which were all prevented by administration of AP-Cav.
Conclusions: Short term administration of a caveolin-based cell-permeable peptide (AP-Cav) to MCT rats prevents the development of pulmonary artery medial hypertrophy, PH and RVH.