Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

Jean François Jasmin, Isabelle Mercier, Jocelyn Dupuis, Herbert B. Tanowitz, Michael P. Lisanti

Research output: Contribution to journalArticle

77 Citations (Scopus)

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. METHODS AND 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 · kg · d), or a peptide consisting of the Cav-1-scaffolding domain coupled to AP (AP-Cav; 2.5 mg · kg · d) 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.

Original languageEnglish (US)
Pages (from-to)912-920
Number of pages9
JournalCirculation
Volume114
Issue number9
DOIs
StatePublished - Aug 2006

Fingerprint

Monocrotaline
Right Ventricular Hypertrophy
Caveolin 1
Pulmonary Hypertension
Peptides
Ventricular Pressure
Hypertrophy
Pulmonary Artery
Cyclin D3
Caveolins
Blood Pressure
Lung
Injections
Cyclin D1
Drosophila
Proteins
Transcription Factors
Up-Regulation
Animal Models

Keywords

  • Caveolin
  • Hypertension, pulmonary
  • Hypertrophy
  • Remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. / Jasmin, Jean François; Mercier, Isabelle; Dupuis, Jocelyn; Tanowitz, Herbert B.; Lisanti, Michael P.

In: Circulation, Vol. 114, No. 9, 08.2006, p. 912-920.

Research output: Contribution to journalArticle

Jasmin, Jean François ; Mercier, Isabelle ; Dupuis, Jocelyn ; Tanowitz, Herbert B. ; Lisanti, Michael P. / Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. In: Circulation. 2006 ; Vol. 114, No. 9. pp. 912-920.
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T1 - Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

AU - Jasmin, Jean François

AU - Mercier, Isabelle

AU - Dupuis, Jocelyn

AU - Tanowitz, Herbert B.

AU - Lisanti, Michael P.

PY - 2006/8

Y1 - 2006/8

N2 - 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. METHODS AND 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 · kg · d), or a peptide consisting of the Cav-1-scaffolding domain coupled to AP (AP-Cav; 2.5 mg · kg · d) 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.

AB - 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. METHODS AND 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 · kg · d), or a peptide consisting of the Cav-1-scaffolding domain coupled to AP (AP-Cav; 2.5 mg · kg · d) 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.

KW - Caveolin

KW - Hypertension, pulmonary

KW - Hypertrophy

KW - Remodeling

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