Effects of Thiol Protease Inhibitors on Cell Cycle and Proliferation of Vascular Smooth Muscle Cells in Culture
Smooth muscle proliferation is a prominent feature of the vascular response to mechanical injury. Accordingly, modulation of proliferation has important therapeutic implications for angioplasty restenosis. We have identified a subclass of thiol protease inhibitors (TPIs) that reversibly inhibit bovi...
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Veröffentlicht in: | Circulation research 1993-02, Vol.72 (2), p.413-423 |
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description | Smooth muscle proliferation is a prominent feature of the vascular response to mechanical injury. Accordingly, modulation of proliferation has important therapeutic implications for angioplasty restenosis. We have identified a subclass of thiol protease inhibitors (TPIs) that reversibly inhibit bovine aortic smooth muscle cell (BASMC) proliferation in vitro. To define the nature of this inhibition, an evaluation of selected steps in the cell cycle was undertaken. Treatment of BASMCs with benzyloxycarbonyl-Leu-norleucinal (calpeptin) at 100 μM and acetyl-Leu-Leu-norleucinal (TPI-1) at 50 μM was shown to cause a block of platelet-derived growth factor-BB as well as serum-inducible cell cycle progression at a point before the G1-S boundary, reducing the percentage of bromo-deoxyuridine-positive cells from 87% to 5% over a 24-hour labeling period. Addition of TPI-1 at various times after serum addition to serum-deprived BASMCs showed 80%1 of the maximal block of DNA synthesis even when added 6 hours after serum. The cell cycle progression block was gradually lost as the delay from serum to TPI-1 application was increased from 6 to 12 hours. By Northern analysis of mRNA after serum addition, TPI-1 caused a fourfold decrease in the transient elevation of fos and myc proto-oncogene as well as a decrease in the levels of both muscle and nonmuscle actin mRNA induced early after serum addition. Flow cytometric analysis of DNA content and synthesis in BASMCs treated with TPI-1 or calpeptin additionally revealed the presence of a distinct cell cycle block in the G2-M compartment. In the aggregate, these results suggest the existence of more than one molecular site potentially involved in inhibition by TPI of cell cycling in BASMCs. |
doi_str_mv | 10.1161/01.RES.72.2.413 |
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Accordingly, modulation of proliferation has important therapeutic implications for angioplasty restenosis. We have identified a subclass of thiol protease inhibitors (TPIs) that reversibly inhibit bovine aortic smooth muscle cell (BASMC) proliferation in vitro. To define the nature of this inhibition, an evaluation of selected steps in the cell cycle was undertaken. Treatment of BASMCs with benzyloxycarbonyl-Leu-norleucinal (calpeptin) at 100 μM and acetyl-Leu-Leu-norleucinal (TPI-1) at 50 μM was shown to cause a block of platelet-derived growth factor-BB as well as serum-inducible cell cycle progression at a point before the G1-S boundary, reducing the percentage of bromo-deoxyuridine-positive cells from 87% to 5% over a 24-hour labeling period. Addition of TPI-1 at various times after serum addition to serum-deprived BASMCs showed 80%1 of the maximal block of DNA synthesis even when added 6 hours after serum. The cell cycle progression block was gradually lost as the delay from serum to TPI-1 application was increased from 6 to 12 hours. By Northern analysis of mRNA after serum addition, TPI-1 caused a fourfold decrease in the transient elevation of fos and myc proto-oncogene as well as a decrease in the levels of both muscle and nonmuscle actin mRNA induced early after serum addition. Flow cytometric analysis of DNA content and synthesis in BASMCs treated with TPI-1 or calpeptin additionally revealed the presence of a distinct cell cycle block in the G2-M compartment. In the aggregate, these results suggest the existence of more than one molecular site potentially involved in inhibition by TPI of cell cycling in BASMCs.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.RES.72.2.413</identifier><identifier>PMID: 8418992</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Animals ; Biological and medical sciences ; Blood vessels and receptors ; Blotting, Northern ; Calpain - antagonists & inhibitors ; Cattle ; Cell Cycle - drug effects ; Cell Division - drug effects ; Cells, Cultured ; Cysteine Proteinase Inhibitors - pharmacology ; Dipeptides - pharmacology ; DNA - analysis ; Fundamental and applied biological sciences. Psychology ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - drug effects ; Vertebrates: cardiovascular system</subject><ispartof>Circulation research, 1993-02, Vol.72 (2), p.413-423</ispartof><rights>1993 American Heart Association, Inc.</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4438-5679bd7a9881ffff4c23e4dbd031e2b1bec5caf0ca192b99a594ee3b4e2e68723</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3673,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4722894$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8418992$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>March, Keith L</creatorcontrib><creatorcontrib>Wilensky, Robert L</creatorcontrib><creatorcontrib>Roeske, Roger W</creatorcontrib><creatorcontrib>Hathaway, David R</creatorcontrib><title>Effects of Thiol Protease Inhibitors on Cell Cycle and Proliferation of Vascular Smooth Muscle Cells in Culture</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>Smooth muscle proliferation is a prominent feature of the vascular response to mechanical injury. Accordingly, modulation of proliferation has important therapeutic implications for angioplasty restenosis. We have identified a subclass of thiol protease inhibitors (TPIs) that reversibly inhibit bovine aortic smooth muscle cell (BASMC) proliferation in vitro. To define the nature of this inhibition, an evaluation of selected steps in the cell cycle was undertaken. Treatment of BASMCs with benzyloxycarbonyl-Leu-norleucinal (calpeptin) at 100 μM and acetyl-Leu-Leu-norleucinal (TPI-1) at 50 μM was shown to cause a block of platelet-derived growth factor-BB as well as serum-inducible cell cycle progression at a point before the G1-S boundary, reducing the percentage of bromo-deoxyuridine-positive cells from 87% to 5% over a 24-hour labeling period. Addition of TPI-1 at various times after serum addition to serum-deprived BASMCs showed 80%1 of the maximal block of DNA synthesis even when added 6 hours after serum. The cell cycle progression block was gradually lost as the delay from serum to TPI-1 application was increased from 6 to 12 hours. By Northern analysis of mRNA after serum addition, TPI-1 caused a fourfold decrease in the transient elevation of fos and myc proto-oncogene as well as a decrease in the levels of both muscle and nonmuscle actin mRNA induced early after serum addition. Flow cytometric analysis of DNA content and synthesis in BASMCs treated with TPI-1 or calpeptin additionally revealed the presence of a distinct cell cycle block in the G2-M compartment. In the aggregate, these results suggest the existence of more than one molecular site potentially involved in inhibition by TPI of cell cycling in BASMCs.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood vessels and receptors</subject><subject>Blotting, Northern</subject><subject>Calpain - antagonists & inhibitors</subject><subject>Cattle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Cells, Cultured</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>Dipeptides - pharmacology</subject><subject>DNA - analysis</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kdFrFDEQxoMo9aw--yTkQXzbbSbJXjaPcly1UFFs9TVksxN2NbepSZbS_94cdzQwhOH7fcPwDSHvgbUAW7hi0P7c37WKt7yVIF6QDXRcNrJT8JJsGGO6UUKw1-RNzn8YAym4viAXvYRea74hce89upJp9PR-mmOgP1IsaDPSm2Wah7nEVMWF7jAEuntyAaldxiMVZo_JlrmK1fzbZrcGm-jdIcYy0W9rPrJHW6Zz9a-hrAnfklfehozvzv8l-XW9v999bW6_f7nZfb5tnJSib7qt0sOorO578PVJxwXKcRiZAOQDDOg6Zz1zFjQftLadlohikMhx2ysuLsmn09yHFP-tmIs5zNnVZeyCcc1GdR1XCvoKXp1Al2LOCb15SPPBpicDzBwjNgxMjdgobripEVfHh_PodTjg-MyfM636x7NeI7HBJ7u4OT9jUnHea1kxecIeYyiY8t-wPmIyE9pQJlMvxwQD3oDWgvHaNbXqvv8BhbCURg</recordid><startdate>199302</startdate><enddate>199302</enddate><creator>March, Keith L</creator><creator>Wilensky, Robert L</creator><creator>Roeske, Roger W</creator><creator>Hathaway, David R</creator><general>American Heart Association, Inc</general><general>Lippincott</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>7X8</scope></search><sort><creationdate>199302</creationdate><title>Effects of Thiol Protease Inhibitors on Cell Cycle and Proliferation of Vascular Smooth Muscle Cells in Culture</title><author>March, Keith L ; Wilensky, Robert L ; Roeske, Roger W ; Hathaway, David R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4438-5679bd7a9881ffff4c23e4dbd031e2b1bec5caf0ca192b99a594ee3b4e2e68723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood vessels and receptors</topic><topic>Blotting, Northern</topic><topic>Calpain - antagonists & inhibitors</topic><topic>Cattle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Cells, Cultured</topic><topic>Cysteine Proteinase Inhibitors - pharmacology</topic><topic>Dipeptides - pharmacology</topic><topic>DNA - analysis</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>March, Keith L</creatorcontrib><creatorcontrib>Wilensky, Robert L</creatorcontrib><creatorcontrib>Roeske, Roger W</creatorcontrib><creatorcontrib>Hathaway, David R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>March, Keith L</au><au>Wilensky, Robert L</au><au>Roeske, Roger W</au><au>Hathaway, David R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Thiol Protease Inhibitors on Cell Cycle and Proliferation of Vascular Smooth Muscle Cells in Culture</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>1993-02</date><risdate>1993</risdate><volume>72</volume><issue>2</issue><spage>413</spage><epage>423</epage><pages>413-423</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>Smooth muscle proliferation is a prominent feature of the vascular response to mechanical injury. Accordingly, modulation of proliferation has important therapeutic implications for angioplasty restenosis. We have identified a subclass of thiol protease inhibitors (TPIs) that reversibly inhibit bovine aortic smooth muscle cell (BASMC) proliferation in vitro. To define the nature of this inhibition, an evaluation of selected steps in the cell cycle was undertaken. Treatment of BASMCs with benzyloxycarbonyl-Leu-norleucinal (calpeptin) at 100 μM and acetyl-Leu-Leu-norleucinal (TPI-1) at 50 μM was shown to cause a block of platelet-derived growth factor-BB as well as serum-inducible cell cycle progression at a point before the G1-S boundary, reducing the percentage of bromo-deoxyuridine-positive cells from 87% to 5% over a 24-hour labeling period. Addition of TPI-1 at various times after serum addition to serum-deprived BASMCs showed 80%1 of the maximal block of DNA synthesis even when added 6 hours after serum. The cell cycle progression block was gradually lost as the delay from serum to TPI-1 application was increased from 6 to 12 hours. By Northern analysis of mRNA after serum addition, TPI-1 caused a fourfold decrease in the transient elevation of fos and myc proto-oncogene as well as a decrease in the levels of both muscle and nonmuscle actin mRNA induced early after serum addition. Flow cytometric analysis of DNA content and synthesis in BASMCs treated with TPI-1 or calpeptin additionally revealed the presence of a distinct cell cycle block in the G2-M compartment. In the aggregate, these results suggest the existence of more than one molecular site potentially involved in inhibition by TPI of cell cycling in BASMCs.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>8418992</pmid><doi>10.1161/01.RES.72.2.413</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biological and medical sciences Blood vessels and receptors Blotting, Northern Calpain - antagonists & inhibitors Cattle Cell Cycle - drug effects Cell Division - drug effects Cells, Cultured Cysteine Proteinase Inhibitors - pharmacology Dipeptides - pharmacology DNA - analysis Fundamental and applied biological sciences. Psychology Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - drug effects Vertebrates: cardiovascular system |
title | Effects of Thiol Protease Inhibitors on Cell Cycle and Proliferation of Vascular Smooth Muscle Cells in Culture |
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