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.
Similar content being viewed by others
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
References
Rabinovitch, M. (2005). Cellular and molecular pathobiology of pulmonary hypertension conference summary. Chest, 128, 642S–646S.
Agarwal, R., & Gomberg-Maitland, M. (2011). Current therapeutics and practical management strategies for pulmonary arterial hypertension. American Heart Journal, 162, 201–213.
Lloyd-Jones, D., Adams, R. J., Brown, T. M., Carnethon, M., Dai, S., De Simone, G., et al. (2010). Heart disease and stroke statistics–2010 update: A report from the American Heart Association. Circulation, 121, e46–e215.
Sehgal, P. B., & Mukhopadhyay, S. (2007). Pulmonary arterial hypertension: A disease of tethers, SNAREs and SNAPs? American Journal of Physiology—Heart and Circulation Physiology, 293, H77–H85.
Huang, J., & Kontos, C. D. (2002). Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 745–751.
Nemenoff, R. A., Simpson, P. A., Furgeson, S. B., Kaplan-Albuquerque, N., Crossno, J., Garl, P. J., et al. (2008). Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1alpha. Circulation Research, 102, 1036–1045.
Nisbet, R. E., Bland, J. M., Kleinhenz, D. J., Mitchell, P. O., Walp, E. R., Sutliff, R. L., et al. (2010). Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. American Journal of Respiratory Cell and Molecular Biology, 42, 482–490.
Gu, J., Tamura, M., & Yamada, K. M. (1998). Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. Journal of Cell Biology, 143, 1375–1383.
Moon, S. K., Kim, H. M., & Kim, C. H. (2004). PTEN induces G1 cell cycle arrest and inhibits MMP-9 expression via the regulation of NF-kappaB and AP-1 in vascular smooth muscle cells. Archives of Biochemistry and Biophysics, 421, 267–276.
Tamguney, T., & Stokoe, D. (2007). New insights into PTEN. Journal of Cell Science, 120, 4071–4079.
Van de Sande, T., De Schrijver, E., Heyns, W., Verhoeven, G., & Swinnen, J. V. (2002). Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Research, 62, 642–646.
Oudit, G. Y., & Penninger, J. M. (2009). Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovascular Research, 82, 250–260.
Oudit, G. Y., Sun, H., Kerfant, B. G., Crackower, M. A., Penninger, J. M., & Backx, P. H. (2004). The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. Journal of Molecular and Cellular Cardiology, 37, 449–471.
Noureddine, H., Gary-Bobo, G., Alifano, M., Marcos, E., Saker, M., Vienney, N., et al. (2011). Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circulation Research, 109, 543–553.
Huang, J., & Kontos, C. D. (2002). PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects. Journal of Biological Chemistry, 277, 10760–10766.
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91, 231–241.
Voelkel, N. F., & Tuder, R. M. (2000). Hypoxia-induced pulmonary vascular remodeling: A model for what human disease? Journal of Clinical Investigation, 106, 733–738.
Moens, A. L., Takimoto, E., Tocchetti, C. G., Chakir, K., Bedja, D., Cormaci, G., et al. (2008). Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: Efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation, 117, 2626–2636.
Feng, N., Hoover, D. B., & Paolocci, N. (2007). Forever young? Nerve growth factor, sympathetic fibers, and right ventricle pressure overload. Circulation Research, 100, 1670–1672.
Itoh, T., Nagaya, N., Fujii, T., Iwase, T., Nakanishi, N., Hamada, K., et al. (2004). A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats. American Journal of Respiratory and Critical Care Medicine, 169, 34–38.
Selvendiran, K., Kuppusamy, M. L., Bratasz, A., Tong, L., Rivera, B. K., Rink, C., et al. (2009). Inhibition of vascular smooth-muscle cell proliferation and arterial restenosis by HO-3867, a novel synthetic curcuminoid, through up-regulation of PTEN expression. Journal of Pharmacology and Experimental Therapeutics, 329, 959–966.
Selvendiran, K., Tong, L., Vishwanath, S., Bratasz, A., Trigg, N. J., Kutala, V. K., et al. (2007). EF24 induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by increasing PTEN expression. Journal of Biological Chemistry, 282, 28609–28618.
Ashcroft, M., Ludwig, R. L., Woods, D. B., Copeland, T. D., Weber, H. O., MacRae, E. J., et al. (2002). Phosphorylation of HDM2 by Akt. Oncogene, 21, 1955–1962.
Cardone, M. H., Roy, N., Stennicke, H. R., Salvesen, G. S., Franke, T. F., Stanbridge, E., et al. (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science, 282, 1318–1321.
Mayo, L. D., & Donner, D. B. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proceedings of the National Academy of Sciences of the United States of America, 98, 11598–11603.
Mizuno, S., Bogaard, H. J., Voelkel, N. F., Umeda, Y., Kadowaki, M., Ameshima, S., et al. (2009). Hypoxia regulates human lung fibroblast proliferation via p53-dependent and -independent pathways. Respiration Research, 10, 17.
Ozes, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., & Donner, D. B. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature, 401, 82–85.
Robbins, I. M. (2004). Advancing therapy for pulmonary arterial hypertension: Can animal models help? American Journal of Respiratory and Critical Care Medicine, 169, 5–6.
Mizuno, S., Bogaard, H. J., Kraskauskas, D., Alhussaini, A., Gomez-Arroyo, J., Voelkel, N. F., et al. (2011). p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice. American Journal of Physiology Lung Cellular and Molecular Physiology, 300, L753–L761.
Penumathsa, S. V., & Maulik, N. (2009). Resveratrol: A promising agent in promoting cardioprotection against coronary heart disease. Canadian Journal of Physiology and Pharmacology, 87, 275–286.
Chung, J. H., Ostrowski, M. C., Romigh, T., Minaguchi, T., Waite, K. A., & Eng, C. (2006). The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation. Human Molecular Genetics, 15, 2553–2559.
Weng, L. P., Brown, J. L., & Eng, C. (2001). PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Human Molecular Genetics, 10, 599–604.
Chen, L., Zhang, J., Gan, T. X., Chen-Izu, Y., Hasday, J. D., Karmazyn, M., et al. (2008). Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. Journal of Applied Physiology, 104, 218–223.
Kimura, H., Kasahara, Y., Kurosu, K., Sugito, K., Takiguchi, Y., Terai, M., et al. (1998). Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Laboratory Investigation, 78, 571–581.
Hershko, A. (1997). Roles of ubiquitin-mediated proteolysis in cell cycle control. Current Opinion in Cell Biology, 9, 788–799.
Heath, D. (1992). The rat is a poor animal model for the study of human pulmonary hypertension. Cardioscience, 3, 1–6.
Tamura, M., Gu, J., Danen, E. H., Takino, T., Miyamoto, S., & Yamada, K. M. (1999). PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. Journal of Biological Chemistry, 274, 20693–20703.
Huang, J., Niu, X. L., Pippen, A. M., Annex, B. H., & Kontos, C. D. (2005). Adenovirus-mediated intraarterial delivery of PTEN inhibits neointimal hyperplasia. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 354–358.
Osman, N., Ballinger, M. L., Dadlani, H. M., Getachew, R., Burch, M. L., & Little, P. J. (2008). p38 MAP kinase mediated proteoglycan synthesis as a target for the prevention of atherosclerosis. Cardiovasc Hematol Disord Drug Targets, 8, 287–292.
Vidavalur, R., Swarnakar, S., Thirunavukkarasu, M., Samuel, S. M., & Maulik, N. (2008). Ex vivo and in vivo approaches to study mechanisms of cardioprotection targeting ischemia/reperfusion (i/r) injury: Useful techniques for cardiovascular drug discovery. Current Drug Discovery Technologies, 5, 269–278.
Libby, P., Ridker, P. M., & Maseri, A. (2002). Inflammation and atherosclerosis. Circulation, 105, 1135–1143.
Rodriguez, O. C., Lai, E. W., Vissapragada, S., Cromelin, C., Avetian, M., Salinas, P., et al. (2009). A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. American Journal of Pathology, 174, 2051–2060.
Basu, P., Sen, U., Tyagi, N., & Tyagi, S. C. (2010). Blood flow interplays with elastin: collagen and MMP: TIMP ratios to maintain healthy vascular structure and function. Journal of Vascular Health and Risk Management, 6, 215–228.
Perez, J., Torres, R. A., Rocic, P., Cismowski, M. J., Weber, D. S., Darley-Usmar, V. M., et al. (2011). PYK2 signaling is required for PDGF-dependent vascular smooth muscle cell proliferation. American Journal of Physiology—Cell Physiology, 301, C242–C251.
McKinsey, T. A., & Kass, D. A. (2007). Small-molecule therapies for cardiac hypertrophy: Moving beneath the cell surface. Nature Reviews Drug Discovery, 6, 617–635.
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).
Conflict of interest
All authors have no relevant disclosures.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12013-011-9332-z