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Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:715-716
doi: 10.1161/01.ATV.0000019007.74346.FB
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:715.)
© 2002 American Heart Association, Inc.

Editorials

PTEN-uating Restenosis

Stefanie Dimmeler; Andreas M. Zeiher

From the Division of Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.

Correspondence to Stefanie Dimmeler PhD, Division of Molecular Cardiology, Dept. of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de

Within the last few years, the lipid phosphatase PTEN has gained increasing attention.1 Initially described as a tumor suppressor gene, the function of PTEN meanwhile ranges from the regulation of the immune system to the recently established important function in neuronal growth.1,2 On a cellular level, PTEN interferes with cell proliferation, survival, and growth. These effects are not restricted to a certain cell type or species but have been demonstrated from Drosophila to humans and in various cell types including cardiomyocytes.2–4 Consistent with a crucial role for PTEN in the regulation of cell fate, the complete deficiency of PTEN leads to embryonic lethality in mice.5,6 On a molecular level, PTEN dephosphorylates phosphatidylinositol-(3,4,5) trisphosphate [PtdIns (3,4,5)P3], which is formed by the phosphatidylinositol-3-kinase (PI3K).4 Thereby, PTEN antagonizes the diverse downstream signaling effector pathways activated by PI3K-derived phospholipids (Figure).



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  		Schematic illustration of the molecular signaling pathways influenced by PTEN: potential role in regulation of smooth muscle cell proliferation, survival, and apoptosis. PTEN dephosphorylates the PtdIns(3,4,5)P3 and thereby prevents activation of downstream effector pathways including the phosphoinositide-dependent kinases (PDK).

See page 745

Now, in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, the article of Huang and Kontos7 adds a new twist to the multifactorial roles of PTEN. The results of this study suggest that PTEN may comprise a new bullet against restenosis. Restenosis is the most important limitation of balloon angioplasty or stent placement and occurs in 20% to 40% of patients within the first few months after successful intervention.8 The development of restenosis is mainly due to reactivation of the normally quiescent smooth muscle cells, which are proliferating and migrating, resulting in neointimal hyperplasia in response to the injury of the vessel wall induced by the intervention.8 Although the potency of PTEN in vivo remains to be established, overexpression of PTEN was shown to inhibit the key players in restenosis, smooth muscle cells. Thereby, PTEN inhibits smooth muscle cell proliferation and migration and, concomitantly, increases apoptosis induction. PTEN acts upstream of a variety of important proliferative signaling cascades (Figure). The dephosphorylation of phospholipids by PTEN prevents activation of the phosphoinositide-dependent kinases (PDKs), which phosphorylate and activate the protein kinase B/Akt and the p70S6 kinase. Furthermore, PTEN blocks the phospholipid-binding to the pleckstrin homology domain within Akt, which is essential for Akt activation. The inhibition of Akt activation leads to the consequent modulation of multiple downstream effector pathways.9,10 Most of the Akt substrates, which are inhibited by Akt, such as forkhead transcription factors or GSK-3, are involved in regulation of proliferation and apoptosis. Forkhead transcription factors induce the expression of the cell cycle inhibitor p27 as well as the pro-apoptotic proteins Bim or the Fas ligand.11 Moreover, GSK-3 seems to play an important role in vascular remodeling by regulating ß-catenin and cyclin D1 stability.12 Finally, Akt was recently shown to phosphorylate and, thereby, inhibit the antiproliferative activity of p21.13 In addition to the antiproliferative and pro-apoptotic effects of PTEN, smooth muscle cell migration is also blocked by PTEN overexpression.7 The molecular mechanism underlying this inhibitory effect is less clear, but may involve a reduction of focal adhesion kinase expression. However, this could also be a secondary phenomenon, given that apoptosis induction is associated with proteolytic cleavage of focal adhesion kinase.14 An involvement of the Akt pathway on Rac should also be considered. At least in endothelial cells, Akt-dependent phosphorylation of the G-protein coupled–receptor EDG-1 is indispensable for Rac activation and endothelial cell chemotaxis.15

Interestingly, PTEN also interferes with the target of rapamycin (TOR), which is currently one of the most promising therapeutic targets for treatment of restenosis.16 Initial clinical studies demonstrate that inhibition of TOR by rapamycin-releasing stents dramatically reduces restenosis (RAVEL-study).16 Akt is known to phosphorylate and, thereby, activate the kinase TOR.17,18 Thus, PTEN-induced Akt inactivation may prevent TOR phosphorylation and activation. Downstream of TOR, the p70S6 kinase is also regulated by PDK1, a kinase which depends on PTEN-sensitive phospholipids. In addition, another downstream target of TOR, 4E-BP1, can be phosphorylated by Akt.18 Although it is not yet clear whether this model can be directly translated to smooth muscle cells, one may easily imagine that PTEN also blocks several rapamycin-sensitive pathways.

Taken together, a broad spectrum of cellular signaling cascades and smooth muscle cell functions are targeted by PTEN. Such a wide therapeutic range, which targets as many of the biological processes contributing to the development of restenosis, may indeed turn out to be an advantage for PTEN overexpression as an anti-restenosis strategy. However, further studies are required to establish the potency of PTEN overexpression in vivo. As such, the work by Huang and Konto7 marks the beginning of an exciting question.

Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 553, B6). We thank Tina Ott for secretarial help with the manuscript. We would like to apologize for the failure to cite many of the important and relevant studies in this field because of space limitations.

References

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  2. Morrison SJ. PTEN-uating neural growth. Nat Med. 2002; 8: 16–18.[CrossRef][Medline] [Order article via Infotrieve]
  3. Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem. 2001; 276: 35786–35793.[Abstract/Free Full Text]
  4. Stambolic V, Suzuki A, de la Pompa J, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95: 29–39.[CrossRef][Medline] [Order article via Infotrieve]
  5. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998; 8: 1169–1178.[CrossRef][Medline] [Order article via Infotrieve]
  6. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. PTEN is essential for embryonic development and tumour suppression. Nat Genet. 1998; 19: 348–355.[CrossRef][Medline] [Order article via Infotrieve]
  7. Huang J, Kontos CD. Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. Arterioscler Thromb Vasc Biol. 2002; 22: 745–751.[Abstract/Free Full Text]
  8. Bennett MR, O’Sullivan M. Mechanisms of angioplasty and stent restenosis: implications for design of rational therapy. Pharmacol Ther. 2001; 91: 149–166.[CrossRef][Medline] [Order article via Infotrieve]
  9. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999; 13: 2905–2927.[Free Full Text]
  10. Dimmeler S, Zeiher AM. Akt takes center stage in angiogenesis signaling. Circ Res. 2000; 86: 4–5.[Free Full Text]
  11. Kops GJ, Burgering BM. Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med. 1999; 77: 656–665.[CrossRef][Medline] [Order article via Infotrieve]
  12. Wang X, Xiao Y, Mou Y, Zhao Y, Blankesteijn WM, Hall JL. A role for the beta-catenin/T-cell factor signaling cascade in vascular remodeling. Circ Res. 2002; 90: 340–347.[Abstract/Free Full Text]
  13. Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, Dimmeler S. Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol. 2001; 21: 5644–5657.[Abstract/Free Full Text]
  14. Levkau B, Herren B, Koyama H, Ross R, Raines EW. Caspase-mediated cleavage of focal adhesion kinase pp125FAK and disassembly of focal adhesions in human endothelial cell apoptosis. J Exp Med. 1998; 187: 579–586.[Abstract/Free Full Text]
  15. Lee MJ, Thangada S, Paik JH, Sapkota GP, Ancellin N, Chae SS, Wu M, Morales-Ruiz M, Sessa WC, Alessi DR, Hla T. Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol Cell. 2001; 8: 693–704.[CrossRef][Medline] [Order article via Infotrieve]
  16. Fox R. American Heart Association 2001 scientific sessions: late-breaking science-drug-eluting stents. Circulation. 2001; 104: E9052.
  17. Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1998; 95: 7772–7777.[Abstract/Free Full Text]
  18. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell. 2000; 103: 253–262.[CrossRef][Medline] [Order article via Infotrieve]




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