Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung

Yazhini Ravi, Karuppaiyah Selvendiran, Shan K. Naidu, Sarath Meduru, Lucas A. Citro, Balázs Bognár, Mahmood Khan, Tamás Kálai, Kálmán Hideg, Periannan Kuppusamy, Chittoor Sai Sudhakar

Research output: Contribution to journalArticle

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Abstract

Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF.

Original languageEnglish (US)
Pages (from-to)593-601
Number of pages9
JournalHypertension
Volume61
Issue number3
DOIs
StatePublished - Mar 1 2013

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Peroxynitrous Acid
Pulmonary Hypertension
Down-Regulation
Heart Failure
Lung
Pulmonary Artery
Smooth Muscle Myocytes
Cell Proliferation
Pressure
Chromosomes, Human, Pair 10
Vascular Smooth Muscle
Phosphoric Monoester Hydrolases
Ligation
Real-Time Polymerase Chain Reaction
Coronary Vessels
Oxidative Stress
Hemodynamics
Western Blotting

All Science Journal Classification (ASJC) codes

  • Internal Medicine

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Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung. / Ravi, Yazhini; Selvendiran, Karuppaiyah; Naidu, Shan K.; Meduru, Sarath; Citro, Lucas A.; Bognár, Balázs; Khan, Mahmood; Kálai, Tamás; Hideg, Kálmán; Kuppusamy, Periannan; Sai Sudhakar, Chittoor.

In: Hypertension, Vol. 61, No. 3, 01.03.2013, p. 593-601.

Research output: Contribution to journalArticle

Ravi, Y, Selvendiran, K, Naidu, SK, Meduru, S, Citro, LA, Bognár, B, Khan, M, Kálai, T, Hideg, K, Kuppusamy, P & Sai Sudhakar, C 2013, 'Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung', Hypertension, vol. 61, no. 3, pp. 593-601. https://doi.org/10.1161/HYPERTENSIONAHA.111.00514
Ravi, Yazhini ; Selvendiran, Karuppaiyah ; Naidu, Shan K. ; Meduru, Sarath ; Citro, Lucas A. ; Bognár, Balázs ; Khan, Mahmood ; Kálai, Tamás ; Hideg, Kálmán ; Kuppusamy, Periannan ; Sai Sudhakar, Chittoor. / Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung. In: Hypertension. 2013 ; Vol. 61, No. 3. pp. 593-601.
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abstract = "Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF.",
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AU - Meduru, Sarath

AU - Citro, Lucas A.

AU - Bognár, Balázs

AU - Khan, Mahmood

AU - Kálai, Tamás

AU - Hideg, Kálmán

AU - Kuppusamy, Periannan

AU - Sai Sudhakar, Chittoor

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N2 - Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF.

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