Sensitivity to Fas-Mediated Apoptosis Is Determined Below Receptor Level in Human Vascular Smooth Muscle Cells
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...
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| Veröffentlicht in: | Circulation research 2000-05, Vol.86 (10), p.1038-1046 |
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| creator | Chan, Shiu-Wan Hegyi, Laszlo Scott, Stephen Cary, Nathaniel R. B Weissberg, Peter L Bennett, Martin R |
| description | 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 |
| doi_str_mv | 10.1161/01.res.86.10.1038 |
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B ; Weissberg, Peter L ; Bennett, Martin R</creator><creatorcontrib>Chan, Shiu-Wan ; Hegyi, Laszlo ; Scott, Stephen ; Cary, Nathaniel R. B ; Weissberg, Peter L ; Bennett, Martin R</creatorcontrib><description>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.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.res.86.10.1038</identifier><identifier>PMID: 10827133</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Adaptor Proteins, Signal Transducing ; Apoptosis - physiology ; Arteriosclerosis - metabolism ; Biological and medical sciences ; Carrier Proteins - metabolism ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Caspases - metabolism ; Cells, Cultured ; Culture Media, Serum-Free ; Drug Resistance ; fas Receptor - metabolism ; fas Receptor - physiology ; Fas-Associated Death Domain Protein ; Fundamental and applied biological sciences. Psychology ; Heart ; Humans ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - physiology ; Signal Transduction ; Vertebrates: cardiovascular system</subject><ispartof>Circulation research, 2000-05, Vol.86 (10), p.1038-1046</ispartof><rights>2000 American Heart Association, Inc.</rights><rights>2000 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. May 26, 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5458-35a265b0edda9ddd552a2e72a87cc2e5eb070dabedf8feac2a8f3abd3f45a7213</citedby><cites>FETCH-LOGICAL-c5458-35a265b0edda9ddd552a2e72a87cc2e5eb070dabedf8feac2a8f3abd3f45a7213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1404696$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10827133$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chan, Shiu-Wan</creatorcontrib><creatorcontrib>Hegyi, Laszlo</creatorcontrib><creatorcontrib>Scott, Stephen</creatorcontrib><creatorcontrib>Cary, Nathaniel R. B</creatorcontrib><creatorcontrib>Weissberg, Peter L</creatorcontrib><creatorcontrib>Bennett, Martin R</creatorcontrib><title>Sensitivity to Fas-Mediated Apoptosis Is Determined Below Receptor Level in Human Vascular Smooth Muscle Cells</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Apoptosis - physiology</subject><subject>Arteriosclerosis - metabolism</subject><subject>Biological and medical sciences</subject><subject>Carrier Proteins - metabolism</subject><subject>Caspase 3</subject><subject>Caspase 8</subject><subject>Caspase 9</subject><subject>Caspases - metabolism</subject><subject>Cells, Cultured</subject><subject>Culture Media, Serum-Free</subject><subject>Drug Resistance</subject><subject>fas Receptor - metabolism</subject><subject>fas Receptor - physiology</subject><subject>Fas-Associated Death Domain Protein</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Heart</subject><subject>Humans</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - physiology</subject><subject>Signal Transduction</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU9vEzEQxS0EoqHwAbggCyFuG_x3d3MsoaWVUiE1wNVy7FnFxbtOPbuN-u1xSCQQpxm9-c3oaR4hbzmbc17zT4zPM-C8recHhcn2GZlxLVSldMOfkxljbFE1UrIz8grxnjGupFi8JGectaLhUs7IsIYBwxgew_hEx0SvLFa34IMdwdOLXdqNCQPSG6RfYITch6HonyGmPb0DB2Wc6QoeIdIw0OuptwP9adFN0Wa67lMat_R2QheBLiFGfE1edDYivDnVc_Lj6vL78rpafft6s7xYVU4r3VZSW1HrDQPv7cJ7r7WwAhph28Y5ARo2rGHebsB3bQfWlUEn7cbLTmnbCC7Pycfj3V1ODxPgaPqArjiwA6QJTcO5qqWQBXz_H3ifpjwUb0ZwobhuG1EgfoRcTogZOrPLobf5yXBmDkkYxs3d5dq09R-lJFF23p0OT5se_D8bx9cX4MMJKP-ysct2cAH_coqpelEXTB2xfYolAPwVpz1kswUbx60pCTPJuKjEodOiZtWhaeVvQPChuQ</recordid><startdate>20000526</startdate><enddate>20000526</enddate><creator>Chan, Shiu-Wan</creator><creator>Hegyi, Laszlo</creator><creator>Scott, Stephen</creator><creator>Cary, Nathaniel R. B</creator><creator>Weissberg, Peter L</creator><creator>Bennett, Martin R</creator><general>American Heart Association, Inc</general><general>Lippincott</general><general>Lippincott Williams & Wilkins Ovid Technologies</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>20000526</creationdate><title>Sensitivity to Fas-Mediated Apoptosis Is Determined Below Receptor Level in Human Vascular Smooth Muscle Cells</title><author>Chan, Shiu-Wan ; Hegyi, Laszlo ; Scott, Stephen ; Cary, Nathaniel R. B ; Weissberg, Peter L ; Bennett, Martin R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5458-35a265b0edda9ddd552a2e72a87cc2e5eb070dabedf8feac2a8f3abd3f45a7213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Apoptosis - physiology</topic><topic>Arteriosclerosis - metabolism</topic><topic>Biological and medical sciences</topic><topic>Carrier Proteins - metabolism</topic><topic>Caspase 3</topic><topic>Caspase 8</topic><topic>Caspase 9</topic><topic>Caspases - metabolism</topic><topic>Cells, Cultured</topic><topic>Culture Media, Serum-Free</topic><topic>Drug Resistance</topic><topic>fas Receptor - metabolism</topic><topic>fas Receptor - physiology</topic><topic>Fas-Associated Death Domain Protein</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Heart</topic><topic>Humans</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - physiology</topic><topic>Signal Transduction</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chan, Shiu-Wan</creatorcontrib><creatorcontrib>Hegyi, Laszlo</creatorcontrib><creatorcontrib>Scott, Stephen</creatorcontrib><creatorcontrib>Cary, Nathaniel R. 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B</au><au>Weissberg, Peter L</au><au>Bennett, Martin R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sensitivity to Fas-Mediated Apoptosis Is Determined Below Receptor Level in Human Vascular Smooth Muscle Cells</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2000-05-26</date><risdate>2000</risdate><volume>86</volume><issue>10</issue><spage>1038</spage><epage>1046</epage><pages>1038-1046</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><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.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>10827133</pmid><doi>10.1161/01.res.86.10.1038</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing Apoptosis - physiology Arteriosclerosis - metabolism Biological and medical sciences Carrier Proteins - metabolism Caspase 3 Caspase 8 Caspase 9 Caspases - metabolism Cells, Cultured Culture Media, Serum-Free Drug Resistance fas Receptor - metabolism fas Receptor - physiology Fas-Associated Death Domain Protein Fundamental and applied biological sciences. Psychology Heart Humans Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - physiology Signal Transduction Vertebrates: cardiovascular system |
| title | Sensitivity to Fas-Mediated Apoptosis Is Determined Below Receptor Level in Human Vascular Smooth Muscle Cells |
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