This Article Full Text Full Text (PDF) Methods Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, S.-W. Articles by Bennett, M. R. Search for Related Content PubMed PubMed Citation Articles by Chan, S.-W. Articles by Bennett, M. R. Related Collections Apoptosis Smooth muscle proliferation and differentiation Mechanism of atherosclerosis/growth factors

(Circulation Research. 2000;86:1038.)
© 2000 American Heart Association, Inc.

Molecular Medicine

Sensitivity to Fas-Mediated Apoptosis Is Determined Below Receptor Level in Human Vascular Smooth Muscle Cells

Shiu-Wan Chan, Laszlo Hegyi, Stephen Scott, Nathaniel R. B. Cary, Peter L. Weissberg, Martin R. Bennett

From the Unit of Cardiovascular Medicine (S.-W.C., L.H., S.S., P.L.W., M.R.B.), Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital; and Department of Histopathology (N.R.B.C.), Papworth Hospital, Papworth Everard, Cambridge, UK.

Correspondence to Martin R. Bennett, Unit of Cardiovascular Medicine, Box 110, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail mrb{at}mole.bio.cam.ac.uk

Abstract—Despite Fas expression, many cells resist Fas-induced apoptosis. Although differences in surface Fas expression can explain Fas resistance, multiple proteins below receptor level also inhibit Fas-induced apoptosis. To examine the mechanism of Fas resistance, we studied Fas-induced apoptosis in human medial vascular smooth muscle cells (VSMCs) from healthy coronary arteries. VSMCs showed marked heterogeneity to Fas-induced apoptosis, exhibiting both Fas-resistant (98.1±2.3% viable, n=4, P=NS) and Fas-sensitive (31.3±2.6% viable, n=3, P<0.01) cells. Fas-resistant VSMCs expressed surface Fas and could recruit RIP, indicating that functional receptor complexes were formed. However, Fas-resistant cells showed reduced expression of FADD, Fas ligand, and caspases 3, 7, and 8 and increased expression of FLIP and c-IAP-1. Fas-induced apoptosis was associated with cleavage of caspase 3 and blocked by inhibitors of caspase 3 or 8 but not caspase 1, 6, or 7. Selective inhibition of caspase 3 or 8 by antisense transfection inhibited Fas-induced apoptosis, but their reexpression could not rescue the Fas-resistant phenotype. In vivo, medial VSMCs showed marked heterogeneity of expression of caspase 3. We conclude that Fas sensitivity is determined not only by expression of surface Fas but by differential expression of Fas-signaling proteins below receptor level. Subpopulations of cells within the same tissue have different sensitivities to apoptosis, determined by expression of specific death-signaling proteins.

Key Words: vascular smooth muscle cell • apoptosis • remodeling

This article has been cited by other articles:

				D. Allard, N. Figg, M. R. Bennett, and T. D. Littlewood Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3 J. Biol. Chem., July 11, 2008; 283(28): 19739 - 19747. [Abstract] [Full Text] [PDF]

				V. I. Patel, S. Daniel, C. R. Longo, G. V. Shrikhande, S. T. Scali, E. Czismadia, C. M. Groft, T. Shukri, C. Motley-Dore, H. E. Ramsey, et al. A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia FASEB J, July 1, 2006; 20(9): 1418 - 1430. [Abstract] [Full Text] [PDF]

				D. Rosner, V. Stoneman, T. Littlewood, N. McCarthy, N. Figg, Y. Wang, G. Tellides, and M. Bennett Interferon-{gamma} Induces Fas Trafficking and Sensitization to Apoptosis in Vascular Smooth Muscle Cells via a PI3K- and Akt-Dependent Mechanism Am. J. Pathol., June 1, 2006; 168(6): 2054 - 2063. [Abstract] [Full Text] [PDF]

				C. M. Matter, C. E. Chadjichristos, P. Meier, T. von Lukowicz, C. Lohmann, P. K. Schuler, D. Zhang, B. Odermatt, E. Hofmann, T. Brunner, et al. Role of Endogenous Fas (CD95/Apo-1) Ligand in Balloon-Induced Apoptosis, Inflammation, and Neointima Formation Circulation, April 18, 2006; 113(15): 1879 - 1887. [Abstract] [Full Text] [PDF]

				T. Urbanek, B. Skop, K. Ziaja, T. Wilczok, R. Wiaderkiewicz, A. Pal/asz, U. Mazurek, and E. Wielgus Sapheno-Femoral Junction Pathology: Molecular Mechanism of Saphenous Vein Incompetence Clinical and Applied Thrombosis/Hemostasis, October 1, 2004; 10(4): 311 - 321. [Abstract] [PDF]

				H. Hao, G. Gabbiani, and M.-L. Bochaton-Piallat Arterial Smooth Muscle Cell Heterogeneity: Implications for Atherosclerosis and Restenosis Development Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1510 - 1520. [Abstract] [Full Text] [PDF]

				W. Martinet, D. M. Schrijvers, G. R.Y. De Meyer, J. Thielemans, M. W.M. Knaapen, A. G. Herman, and M. M. Kockx Gene Expression Profiling of Apoptosis-Related Genes in Human Atherosclerosis: Upregulation of Death-Associated Protein Kinase Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2023 - 2029. [Abstract] [Full Text] [PDF]

				S.-C. Huang, M.-J. Tang, K.-F. Hsu, Y.-M. Cheng, and C.-Y. Chou Fas and Its Ligand, Caspases, and Bcl-2 Expression in Gonadotropin-Releasing Hormone Agonist-Treated Uterine Leiomyoma J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4580 - 4586. [Abstract] [Full Text] [PDF]

				W. Wang, C. Z. Prince, Y. Mou, and M. J. Pollman Notch3 Signaling in Vascular Smooth Muscle Cells Induces c-FLIP Expression via ERK/MAPK Activation. RESISTANCE TO Fas LIGAND-INDUCED APOPTOSIS J. Biol. Chem., June 7, 2002; 277(24): 21723 - 21729. [Abstract] [Full Text] [PDF]

				G. Yaniv, M. Shilkrut, R. Lotan, G. Berke, S. Larisch, and O. Binah Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes Cardiovasc Res, June 1, 2002; 54(3): 611 - 623. [Abstract] [Full Text] [PDF]

				A. J. Belanger, A. Scaria, H. Lu, J. A. Sullivan, S. H. Cheng, R. J. Gregory, and C. Jiang Fas ligand/Fas-mediated apoptosis in human coronary artery smooth muscle cells: therapeutic implications of fratricidal mode of action Cardiovasc Res, September 1, 2001; 51(4): 749 - 761. [Abstract] [Full Text] [PDF]

				A. Orlandi, A. Francesconi, D. Cocchia, A. Corsini, and L. G. Spagnoli Phenotypic Heterogeneity Influences Apoptotic Susceptibility to Retinoic Acid and cis-Platinum of Rat Arterial Smooth Muscle Cells In Vitro : Implications for the Evolution of Experimental Intimal Thickening Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1118 - 1123. [Abstract] [Full Text] [PDF]

				S. A. Fisher, B. L. Langille, and D. Srivastava Apoptosis During Cardiovascular Development Circ. Res., November 10, 2000; 87(10): 856 - 864. [Abstract] [Full Text] [PDF]

				G. H. Gibbons and M. J. Pollman Death Receptors, Intimal Disease, and Gene Therapy : Are Therapies That Modify Cell Fate Moving too Fas? Circ. Res., May 26, 2000; 86(10): 1009 - 1012. [Full Text] [PDF]

				M. Hernandez, L. Fuentes, F. J. Fernandez Aviles, M. S. Crespo, and M. L. Nieto Secretory Phospholipase A2 Elicits Proinflammatory Changes and Upregulates the Surface Expression of Fas Ligand in Monocytic Cells: Potential Relevance for Atherogenesis Circ. Res., January 11, 2002; 90(1): 38 - 45. [Abstract] [Full Text] [PDF]