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Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension

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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.

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Abbreviations

LAD:

Left anterior descending coronary artery

LVSP:

Left ventricular systolic pressure

MAP:

Pulmonary arterial pressure

MAP:

Mean aortic pressure

MCT:

Monocrotaline

MRI:

Magnetic resonance imaging

PH:

Pulmonary hypertension

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

RVSP:

Right ventricular systolic pressure

SMC:

Smooth muscle cell

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Acknowledgments

This study was supported by NIH grant HL095066. The authors thank Alex Dayton and Lakshmi Kuppusamy for providing cells and their help with some measurements. The text embodied in this manuscript was presented at the American Heart Association Annual Scientific Meeting, Nov 13-17, 2010, Chicago, USA, and the abstract is published in Circulation 122: A20181 (2010).

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Correspondence to Chittoor B. Sai-Sudhakar.

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Ravi, Y., Selvendiran, K., Meduru, S. et al. Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension. Cell Biochem Biophys 67, 363–372 (2013). https://doi.org/10.1007/s12013-011-9332-z

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