Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis
OBJECTIVE—We previously demonstrated that upregulation of intermediate-conductance Ca-activated K channels (KCa3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective of the present study was to determine the role of KCa3.1 i...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2008-06, Vol.28 (6), p.1084-1089 |
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| container_title | Arteriosclerosis, thrombosis, and vascular biology |
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| creator | Tharp, D L Wamhoff, B R Wulff, H Raman, G Cheong, A Bowles, D K |
| description | OBJECTIVE—We previously demonstrated that upregulation of intermediate-conductance Ca-activated K channels (KCa3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective of the present study was to determine the role of KCa3.1 in the regulation of coronary SMC phenotypic modulation in vivo using a swine model of postangioplasty restenosis.
METHODS AND RESULTS—Balloon angioplasty was performed on coronary arteries of swine using either noncoated or balloons coated with the specific KCa3.1 blocker TRAM-34. Expression of KCa3.1, c-jun, c-fos, repressor element-1 silencing transcription factor (REST), smooth muscle myosin heavy chain (SMMHC), and myocardin was measured using qRT-PCR in isolated medial cells 2 hours and 2 days postangioplasty. KCa3.1, c-jun, and c-fos mRNA levels were increased 2 hours postangioplasty, whereas REST expression decreased. SMMHC expression was unchanged at 2 hours, but decreased 2 days postangioplasty. Use of TRAM-34 coated balloons prevented KCa3.1 upregulation and REST downregulation at 2 hours, SMMHC and myocardin downregulation at 2 days, and attenuated subsequent restenosis 14 and 28 days postangioplasty. Immunohistochemical analysis demonstrated corresponding changes at the protein level.
CONCLUSION—Blockade of KCa3.1 by delivery of TRAM-34 via balloon catheter prevented smooth muscle phenotypic modulation and limited subsequent restenosis. |
| doi_str_mv | 10.1161/ATVBAHA.107.155796 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2652246</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>70772012</sourcerecordid><originalsourceid>FETCH-LOGICAL-h2849-14041a2a3e9262989bbc7bf5806d23ae331fc91090f54a25e4cbd90448ff9823</originalsourceid><addsrcrecordid>eNpVkd9u0zAUxi0EYqPwAlwg38DVUvw3iW-QsjLYRCsmVnEbOc7JYubGJXY69TX2xLhameDiyMfyT993fD6E3lIypzSnH6v1z_PqsppTUsyplIXKn6FTKpnIRM7z56knhcpkLtgJehXCL0KIYIy8RCe05ERRKk7Rw9Ib7fBncHYH4x77Dsce8LeF5nOKz503dzCe4fWPapVxcYavR9jBEAOuzBQBV8Ot9VunQ9xnV0M7GWjxwo9-0EnrZuN97PFqCsYBvu5h8HG_tQavfDs5Ha0fsB5avLQbmxRvYgKCDa_Ri067AG-O5wytv1ysF5fZ8vvXq0W1zHpWCpVRQQTVTHNQLGeqVE1jiqaTJclbxjVwTjujKFGkk0IzCcI0rSJClF2nSsZn6NOj7HZqNtCa9KtRu3o72k0avvba1v-_DLavb_2uZrlkLG14hj4cBUb_e4IQ640NBpzTA_gp1AUpCkbowendv05PFn9TSMD7I6BDSqMb9WBseOIY4UqW_CAkHrl77yKM4c5N9zDWPWgX-_oQL8-JzBghaQnpmqUiiv8BJ6Snyw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>70772012</pqid></control><display><type>article</type><title>Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><source>Journals@Ovid Complete</source><creator>Tharp, D L ; Wamhoff, B R ; Wulff, H ; Raman, G ; Cheong, A ; Bowles, D K</creator><creatorcontrib>Tharp, D L ; Wamhoff, B R ; Wulff, H ; Raman, G ; Cheong, A ; Bowles, D K</creatorcontrib><description>OBJECTIVE—We previously demonstrated that upregulation of intermediate-conductance Ca-activated K channels (KCa3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective of the present study was to determine the role of KCa3.1 in the regulation of coronary SMC phenotypic modulation in vivo using a swine model of postangioplasty restenosis.
METHODS AND RESULTS—Balloon angioplasty was performed on coronary arteries of swine using either noncoated or balloons coated with the specific KCa3.1 blocker TRAM-34. Expression of KCa3.1, c-jun, c-fos, repressor element-1 silencing transcription factor (REST), smooth muscle myosin heavy chain (SMMHC), and myocardin was measured using qRT-PCR in isolated medial cells 2 hours and 2 days postangioplasty. KCa3.1, c-jun, and c-fos mRNA levels were increased 2 hours postangioplasty, whereas REST expression decreased. SMMHC expression was unchanged at 2 hours, but decreased 2 days postangioplasty. Use of TRAM-34 coated balloons prevented KCa3.1 upregulation and REST downregulation at 2 hours, SMMHC and myocardin downregulation at 2 days, and attenuated subsequent restenosis 14 and 28 days postangioplasty. Immunohistochemical analysis demonstrated corresponding changes at the protein level.
CONCLUSION—Blockade of KCa3.1 by delivery of TRAM-34 via balloon catheter prevented smooth muscle phenotypic modulation and limited subsequent restenosis.</description><identifier>ISSN: 1079-5642</identifier><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/ATVBAHA.107.155796</identifier><identifier>PMID: 18309114</identifier><identifier>CODEN: ATVBFA</identifier><language>eng</language><publisher>Philadelphia, PA: American Heart Association, Inc</publisher><subject>Angioplasty, Balloon, Coronary - adverse effects ; Animals ; Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Blood and lymphatic vessels ; Blood vessels and receptors ; Cardiology. Vascular system ; Cell Differentiation - drug effects ; Coronary Stenosis - pathology ; Coronary Stenosis - prevention & control ; Coronary Vessels - drug effects ; Coronary Vessels - metabolism ; Coronary Vessels - pathology ; Disease Models, Animal ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Fundamental and applied biological sciences. Psychology ; Intermediate-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors ; Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism ; Male ; Medical sciences ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - pathology ; Phenotype ; Potassium Channel Blockers - pharmacology ; Proto-Oncogene Proteins c-fos - metabolism ; Proto-Oncogene Proteins c-jun - metabolism ; Pyrazoles - pharmacology ; Swine ; Transcription Factors - metabolism ; Vertebrates: cardiovascular system</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2008-06, Vol.28 (6), p.1084-1089</ispartof><rights>2008 American Heart Association, Inc.</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20395832$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18309114$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tharp, D L</creatorcontrib><creatorcontrib>Wamhoff, B R</creatorcontrib><creatorcontrib>Wulff, H</creatorcontrib><creatorcontrib>Raman, G</creatorcontrib><creatorcontrib>Cheong, A</creatorcontrib><creatorcontrib>Bowles, D K</creatorcontrib><title>Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description>OBJECTIVE—We previously demonstrated that upregulation of intermediate-conductance Ca-activated K channels (KCa3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective of the present study was to determine the role of KCa3.1 in the regulation of coronary SMC phenotypic modulation in vivo using a swine model of postangioplasty restenosis.
METHODS AND RESULTS—Balloon angioplasty was performed on coronary arteries of swine using either noncoated or balloons coated with the specific KCa3.1 blocker TRAM-34. Expression of KCa3.1, c-jun, c-fos, repressor element-1 silencing transcription factor (REST), smooth muscle myosin heavy chain (SMMHC), and myocardin was measured using qRT-PCR in isolated medial cells 2 hours and 2 days postangioplasty. KCa3.1, c-jun, and c-fos mRNA levels were increased 2 hours postangioplasty, whereas REST expression decreased. SMMHC expression was unchanged at 2 hours, but decreased 2 days postangioplasty. Use of TRAM-34 coated balloons prevented KCa3.1 upregulation and REST downregulation at 2 hours, SMMHC and myocardin downregulation at 2 days, and attenuated subsequent restenosis 14 and 28 days postangioplasty. Immunohistochemical analysis demonstrated corresponding changes at the protein level.
CONCLUSION—Blockade of KCa3.1 by delivery of TRAM-34 via balloon catheter prevented smooth muscle phenotypic modulation and limited subsequent restenosis.</description><subject>Angioplasty, Balloon, Coronary - adverse effects</subject><subject>Animals</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Blood vessels and receptors</subject><subject>Cardiology. Vascular system</subject><subject>Cell Differentiation - drug effects</subject><subject>Coronary Stenosis - pathology</subject><subject>Coronary Stenosis - prevention & control</subject><subject>Coronary Vessels - drug effects</subject><subject>Coronary Vessels - metabolism</subject><subject>Coronary Vessels - pathology</subject><subject>Disease Models, Animal</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Intermediate-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors</subject><subject>Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>Phenotype</subject><subject>Potassium Channel Blockers - pharmacology</subject><subject>Proto-Oncogene Proteins c-fos - metabolism</subject><subject>Proto-Oncogene Proteins c-jun - metabolism</subject><subject>Pyrazoles - pharmacology</subject><subject>Swine</subject><subject>Transcription Factors - metabolism</subject><subject>Vertebrates: cardiovascular system</subject><issn>1079-5642</issn><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd9u0zAUxi0EYqPwAlwg38DVUvw3iW-QsjLYRCsmVnEbOc7JYubGJXY69TX2xLhameDiyMfyT993fD6E3lIypzSnH6v1z_PqsppTUsyplIXKn6FTKpnIRM7z56knhcpkLtgJehXCL0KIYIy8RCe05ERRKk7Rw9Ib7fBncHYH4x77Dsce8LeF5nOKz503dzCe4fWPapVxcYavR9jBEAOuzBQBV8Ot9VunQ9xnV0M7GWjxwo9-0EnrZuN97PFqCsYBvu5h8HG_tQavfDs5Ha0fsB5avLQbmxRvYgKCDa_Ri067AG-O5wytv1ysF5fZ8vvXq0W1zHpWCpVRQQTVTHNQLGeqVE1jiqaTJclbxjVwTjujKFGkk0IzCcI0rSJClF2nSsZn6NOj7HZqNtCa9KtRu3o72k0avvba1v-_DLavb_2uZrlkLG14hj4cBUb_e4IQ640NBpzTA_gp1AUpCkbowendv05PFn9TSMD7I6BDSqMb9WBseOIY4UqW_CAkHrl77yKM4c5N9zDWPWgX-_oQL8-JzBghaQnpmqUiiv8BJ6Snyw</recordid><startdate>200806</startdate><enddate>200806</enddate><creator>Tharp, D L</creator><creator>Wamhoff, B R</creator><creator>Wulff, H</creator><creator>Raman, G</creator><creator>Cheong, A</creator><creator>Bowles, D K</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>200806</creationdate><title>Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis</title><author>Tharp, D L ; Wamhoff, B R ; Wulff, H ; Raman, G ; Cheong, A ; Bowles, D K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h2849-14041a2a3e9262989bbc7bf5806d23ae331fc91090f54a25e4cbd90448ff9823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Angioplasty, Balloon, Coronary - adverse effects</topic><topic>Animals</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Blood vessels and receptors</topic><topic>Cardiology. Vascular system</topic><topic>Cell Differentiation - drug effects</topic><topic>Coronary Stenosis - pathology</topic><topic>Coronary Stenosis - prevention & control</topic><topic>Coronary Vessels - drug effects</topic><topic>Coronary Vessels - metabolism</topic><topic>Coronary Vessels - pathology</topic><topic>Disease Models, Animal</topic><topic>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Intermediate-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors</topic><topic>Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscle, Smooth, Vascular - pathology</topic><topic>Phenotype</topic><topic>Potassium Channel Blockers - pharmacology</topic><topic>Proto-Oncogene Proteins c-fos - metabolism</topic><topic>Proto-Oncogene Proteins c-jun - metabolism</topic><topic>Pyrazoles - pharmacology</topic><topic>Swine</topic><topic>Transcription Factors - metabolism</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tharp, D L</creatorcontrib><creatorcontrib>Wamhoff, B R</creatorcontrib><creatorcontrib>Wulff, H</creatorcontrib><creatorcontrib>Raman, G</creatorcontrib><creatorcontrib>Cheong, A</creatorcontrib><creatorcontrib>Bowles, D K</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tharp, D L</au><au>Wamhoff, B R</au><au>Wulff, H</au><au>Raman, G</au><au>Cheong, A</au><au>Bowles, D K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2008-06</date><risdate>2008</risdate><volume>28</volume><issue>6</issue><spage>1084</spage><epage>1089</epage><pages>1084-1089</pages><issn>1079-5642</issn><eissn>1524-4636</eissn><coden>ATVBFA</coden><abstract>OBJECTIVE—We previously demonstrated that upregulation of intermediate-conductance Ca-activated K channels (KCa3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective of the present study was to determine the role of KCa3.1 in the regulation of coronary SMC phenotypic modulation in vivo using a swine model of postangioplasty restenosis.
METHODS AND RESULTS—Balloon angioplasty was performed on coronary arteries of swine using either noncoated or balloons coated with the specific KCa3.1 blocker TRAM-34. Expression of KCa3.1, c-jun, c-fos, repressor element-1 silencing transcription factor (REST), smooth muscle myosin heavy chain (SMMHC), and myocardin was measured using qRT-PCR in isolated medial cells 2 hours and 2 days postangioplasty. KCa3.1, c-jun, and c-fos mRNA levels were increased 2 hours postangioplasty, whereas REST expression decreased. SMMHC expression was unchanged at 2 hours, but decreased 2 days postangioplasty. Use of TRAM-34 coated balloons prevented KCa3.1 upregulation and REST downregulation at 2 hours, SMMHC and myocardin downregulation at 2 days, and attenuated subsequent restenosis 14 and 28 days postangioplasty. Immunohistochemical analysis demonstrated corresponding changes at the protein level.
CONCLUSION—Blockade of KCa3.1 by delivery of TRAM-34 via balloon catheter prevented smooth muscle phenotypic modulation and limited subsequent restenosis.</abstract><cop>Philadelphia, PA</cop><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>18309114</pmid><doi>10.1161/ATVBAHA.107.155796</doi><tpages>6</tpages></addata></record> |
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| subjects | Angioplasty, Balloon, Coronary - adverse effects Animals Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Blood vessels and receptors Cardiology. Vascular system Cell Differentiation - drug effects Coronary Stenosis - pathology Coronary Stenosis - prevention & control Coronary Vessels - drug effects Coronary Vessels - metabolism Coronary Vessels - pathology Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Fundamental and applied biological sciences. Psychology Intermediate-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism Male Medical sciences Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Phenotype Potassium Channel Blockers - pharmacology Proto-Oncogene Proteins c-fos - metabolism Proto-Oncogene Proteins c-jun - metabolism Pyrazoles - pharmacology Swine Transcription Factors - metabolism Vertebrates: cardiovascular system |
| title | Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis |
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