Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension

Yazhini Ravi, Karuppaiyah Selvendiran, Sarath Meduru, Lucas Citro, Shan Naidu, Mahmood Khan, Brian K. Rivera, Chittoor Sai Sudhakar, Periannan Kuppusamy

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10% oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53%; Hypoxia, 40%), pAkt was significantly increased (MCT, 42%; Hypoxia, 55%) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1% oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target.

Original languageEnglish (US)
Pages (from-to)363-372
Number of pages10
JournalCell Biochemistry and Biophysics
Volume67
Issue number2
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Monocrotaline
Pulmonary Hypertension
Muscle
Rats
Tissue
Oxygen
Degradation
Fatty Acid Synthases
Focal Adhesion Protein-Tyrosine Kinases
Cell Cycle Proteins
Cyclin D1
Hemodynamics
Chromosomes
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Lung
Assays
Cells
Modulation
Smooth Muscle Myocytes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension. / Ravi, Yazhini; Selvendiran, Karuppaiyah; Meduru, Sarath; Citro, Lucas; Naidu, Shan; Khan, Mahmood; Rivera, Brian K.; Sai Sudhakar, Chittoor; Kuppusamy, Periannan.

In: Cell Biochemistry and Biophysics, Vol. 67, No. 2, 01.01.2013, p. 363-372.

Research output: Contribution to journalArticle

Ravi, Yazhini ; Selvendiran, Karuppaiyah ; Meduru, Sarath ; Citro, Lucas ; Naidu, Shan ; Khan, Mahmood ; Rivera, Brian K. ; Sai Sudhakar, Chittoor ; Kuppusamy, Periannan. / Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension. In: Cell Biochemistry and Biophysics. 2013 ; Vol. 67, No. 2. pp. 363-372.
@article{3063c1ed7fe0484aac111be0b23e6e42,
title = "Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension",
abstract = "Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10{\%} oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53{\%}; Hypoxia, 40{\%}), pAkt was significantly increased (MCT, 42{\%}; Hypoxia, 55{\%}) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1{\%} oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target.",
author = "Yazhini Ravi and Karuppaiyah Selvendiran and Sarath Meduru and Lucas Citro and Shan Naidu and Mahmood Khan and Rivera, {Brian K.} and {Sai Sudhakar}, Chittoor and Periannan Kuppusamy",
year = "2013",
month = "1",
day = "1",
doi = "10.1007/s12013-011-9332-z",
language = "English (US)",
volume = "67",
pages = "363--372",
journal = "Cell Biochemistry and Biophysics",
issn = "1085-9195",
publisher = "Humana Press",
number = "2",

}

TY - JOUR

T1 - Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension

AU - Ravi, Yazhini

AU - Selvendiran, Karuppaiyah

AU - Meduru, Sarath

AU - Citro, Lucas

AU - Naidu, Shan

AU - Khan, Mahmood

AU - Rivera, Brian K.

AU - Sai Sudhakar, Chittoor

AU - Kuppusamy, Periannan

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10% oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53%; Hypoxia, 40%), pAkt was significantly increased (MCT, 42%; Hypoxia, 55%) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1% oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target.

AB - Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10% oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53%; Hypoxia, 40%), pAkt was significantly increased (MCT, 42%; Hypoxia, 55%) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1% oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target.

UR - http://www.scopus.com/inward/record.url?scp=84886594011&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886594011&partnerID=8YFLogxK

U2 - 10.1007/s12013-011-9332-z

DO - 10.1007/s12013-011-9332-z

M3 - Article

VL - 67

SP - 363

EP - 372

JO - Cell Biochemistry and Biophysics

JF - Cell Biochemistry and Biophysics

SN - 1085-9195

IS - 2

ER -