Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein
Rhabdomyolysis is a severe adverse effect of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin‐induced apoptosis by the dete...
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Veröffentlicht in: | Journal of pharmacy and pharmacology 2005-11, Vol.57 (11), p.1475-1484 |
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creator | Matzno, Sumio Yasuda, Shinya Juman, Sachiko Yamamoto, Yukiko Nagareya-Ishida, Noriko Nakabayashi, Toshikatsu Matsuyama, Kenji Tazuya-Murayama, Keiko |
description | Rhabdomyolysis is a severe adverse effect of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin‐induced apoptosis by the detection of membrane flip‐flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 μm), cerivastatin (3 μm), fluvastatin (3 μm), pravastatin (3 mm), or simvastatin (3 μm)) for 2, 4 or 6 h followed by reacting with FITC‐conjugated annexin V for the detection of initial apoptosis signal (flip‐flop). Various statin‐treated myoblasts were significantly stained with FITC‐annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 μm), membrane‐associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase‐8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin‐related Ras depletion. In conclusion, statin‐induced apoptosis in muscular tissue was directly initiated by the farnesyl‐anchored Ras protein depletion from cell membrane with subsequent apoptosis. |
doi_str_mv | 10.1211/jpp.57.11.0014 |
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This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin‐induced apoptosis by the detection of membrane flip‐flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 μm), cerivastatin (3 μm), fluvastatin (3 μm), pravastatin (3 mm), or simvastatin (3 μm)) for 2, 4 or 6 h followed by reacting with FITC‐conjugated annexin V for the detection of initial apoptosis signal (flip‐flop). Various statin‐treated myoblasts were significantly stained with FITC‐annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 μm), membrane‐associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase‐8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin‐related Ras depletion. In conclusion, statin‐induced apoptosis in muscular tissue was directly initiated by the farnesyl‐anchored Ras protein depletion from cell membrane with subsequent apoptosis.</description><identifier>ISSN: 0022-3573</identifier><identifier>EISSN: 2042-7158</identifier><identifier>DOI: 10.1211/jpp.57.11.0014</identifier><identifier>PMID: 16259781</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Apoptosis ; Atorvastatin Calcium ; Caspase 8 - metabolism ; Cell Line ; Fatty Acids, Monounsaturated - pharmacology ; Flow Cytometry ; Heptanoic Acids - pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Indoles - pharmacology ; Membrane Lipids - metabolism ; Microscopy, Fluorescence ; Myoblasts, Skeletal - drug effects ; Myoblasts, Skeletal - metabolism ; Myoblasts, Skeletal - ultrastructure ; Protein Prenylation ; Pyridines - pharmacology ; Pyrroles - pharmacology ; ras Proteins - metabolism ; Rats ; rho GTP-Binding Proteins - metabolism ; Signal Transduction - drug effects</subject><ispartof>Journal of pharmacy and pharmacology, 2005-11, Vol.57 (11), p.1475-1484</ispartof><rights>2005 Royal Pharmaceutical Society of Great Britain</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4155-1a1eca8597b927ca76fa41645d6fd168fb9e0071b865bd6d74dc40c5d2fd50273</citedby><cites>FETCH-LOGICAL-c4155-1a1eca8597b927ca76fa41645d6fd168fb9e0071b865bd6d74dc40c5d2fd50273</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1211%2Fjpp.57.11.0014$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1211%2Fjpp.57.11.0014$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16259781$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matzno, Sumio</creatorcontrib><creatorcontrib>Yasuda, Shinya</creatorcontrib><creatorcontrib>Juman, Sachiko</creatorcontrib><creatorcontrib>Yamamoto, Yukiko</creatorcontrib><creatorcontrib>Nagareya-Ishida, Noriko</creatorcontrib><creatorcontrib>Nakabayashi, Toshikatsu</creatorcontrib><creatorcontrib>Matsuyama, Kenji</creatorcontrib><creatorcontrib>Tazuya-Murayama, Keiko</creatorcontrib><title>Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein</title><title>Journal of pharmacy and pharmacology</title><addtitle>J Pharm Pharmacol</addtitle><description>Rhabdomyolysis is a severe adverse effect of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin‐induced apoptosis by the detection of membrane flip‐flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 μm), cerivastatin (3 μm), fluvastatin (3 μm), pravastatin (3 mm), or simvastatin (3 μm)) for 2, 4 or 6 h followed by reacting with FITC‐conjugated annexin V for the detection of initial apoptosis signal (flip‐flop). Various statin‐treated myoblasts were significantly stained with FITC‐annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 μm), membrane‐associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase‐8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin‐related Ras depletion. In conclusion, statin‐induced apoptosis in muscular tissue was directly initiated by the farnesyl‐anchored Ras protein depletion from cell membrane with subsequent apoptosis.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Atorvastatin Calcium</subject><subject>Caspase 8 - metabolism</subject><subject>Cell Line</subject><subject>Fatty Acids, Monounsaturated - pharmacology</subject><subject>Flow Cytometry</subject><subject>Heptanoic Acids - pharmacology</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors</subject><subject>Indoles - pharmacology</subject><subject>Membrane Lipids - metabolism</subject><subject>Microscopy, Fluorescence</subject><subject>Myoblasts, Skeletal - drug effects</subject><subject>Myoblasts, Skeletal - metabolism</subject><subject>Myoblasts, Skeletal - ultrastructure</subject><subject>Protein Prenylation</subject><subject>Pyridines - pharmacology</subject><subject>Pyrroles - pharmacology</subject><subject>ras Proteins - metabolism</subject><subject>Rats</subject><subject>rho GTP-Binding Proteins - metabolism</subject><subject>Signal Transduction - drug effects</subject><issn>0022-3573</issn><issn>2042-7158</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM9vFCEYhonR2LV69Wg4eXJGPmaA2aNZ3W1No1VrPBJm-MalZX4IbOoe_N9Ls1s9eoLA87zwvYS8BFYCB3h7Pc-lUCVAyRjUj8iCs5oXCkTzmCwY47yohKpOyLMYrxljSkr5lJyA5GKpGliQP9-SSW4s3Gh3HVpq5mlOU3SRejfe5INbl7Z0wKENZkTamzBi3HuT8tVXE2kcjPd0Q-cwJXQjtTh7TG4a39Bg0hYDTVsz0p-Y9QdtOz3gz8mT3viIL47rKfm-_nC1OisuPm_OV-8uiq4GIQowgJ1p8pfbJVedUbI3NchaWNlbkE3fLjHPBm0jRWulVbXtatYJy3srGFfVKXl9yM3v_tphTHpwsUPv80zTLmrZKAFSQQbLA9iFKcaAvZ6DG0zYa2D6vnCdC9dC6by7LzwLr47Ju3ZA-w8_NpyB6gDcOo_7_8Tpj5dnl2opslUcLBcT_v5rmXCjpaqU0D8-bfSafVnXq6v3elPdAURVnbg</recordid><startdate>200511</startdate><enddate>200511</enddate><creator>Matzno, Sumio</creator><creator>Yasuda, Shinya</creator><creator>Juman, Sachiko</creator><creator>Yamamoto, Yukiko</creator><creator>Nagareya-Ishida, Noriko</creator><creator>Nakabayashi, Toshikatsu</creator><creator>Matsuyama, Kenji</creator><creator>Tazuya-Murayama, Keiko</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</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>200511</creationdate><title>Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein</title><author>Matzno, Sumio ; Yasuda, Shinya ; Juman, Sachiko ; Yamamoto, Yukiko ; Nagareya-Ishida, Noriko ; Nakabayashi, Toshikatsu ; Matsuyama, Kenji ; Tazuya-Murayama, Keiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4155-1a1eca8597b927ca76fa41645d6fd168fb9e0071b865bd6d74dc40c5d2fd50273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Atorvastatin Calcium</topic><topic>Caspase 8 - metabolism</topic><topic>Cell Line</topic><topic>Fatty Acids, Monounsaturated - pharmacology</topic><topic>Flow Cytometry</topic><topic>Heptanoic Acids - pharmacology</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors</topic><topic>Indoles - pharmacology</topic><topic>Membrane Lipids - metabolism</topic><topic>Microscopy, Fluorescence</topic><topic>Myoblasts, Skeletal - drug effects</topic><topic>Myoblasts, Skeletal - metabolism</topic><topic>Myoblasts, Skeletal - ultrastructure</topic><topic>Protein Prenylation</topic><topic>Pyridines - pharmacology</topic><topic>Pyrroles - pharmacology</topic><topic>ras Proteins - metabolism</topic><topic>Rats</topic><topic>rho GTP-Binding Proteins - metabolism</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matzno, Sumio</creatorcontrib><creatorcontrib>Yasuda, Shinya</creatorcontrib><creatorcontrib>Juman, Sachiko</creatorcontrib><creatorcontrib>Yamamoto, Yukiko</creatorcontrib><creatorcontrib>Nagareya-Ishida, Noriko</creatorcontrib><creatorcontrib>Nakabayashi, Toshikatsu</creatorcontrib><creatorcontrib>Matsuyama, Kenji</creatorcontrib><creatorcontrib>Tazuya-Murayama, Keiko</creatorcontrib><collection>Istex</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>Journal of pharmacy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matzno, Sumio</au><au>Yasuda, Shinya</au><au>Juman, Sachiko</au><au>Yamamoto, Yukiko</au><au>Nagareya-Ishida, Noriko</au><au>Nakabayashi, Toshikatsu</au><au>Matsuyama, Kenji</au><au>Tazuya-Murayama, Keiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein</atitle><jtitle>Journal of pharmacy and pharmacology</jtitle><addtitle>J Pharm Pharmacol</addtitle><date>2005-11</date><risdate>2005</risdate><volume>57</volume><issue>11</issue><spage>1475</spage><epage>1484</epage><pages>1475-1484</pages><issn>0022-3573</issn><eissn>2042-7158</eissn><abstract>Rhabdomyolysis is a severe adverse effect of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors (statins). This myopathy is strongly enhanced by the combination with statins and fibrates, another hypolipidaemic agent. We have evaluated the initial step of statin‐induced apoptosis by the detection of membrane flip‐flop using flow cytometric analysis. L6 rat myoblasts were treated with various statins (atorvastatin (3 μm), cerivastatin (3 μm), fluvastatin (3 μm), pravastatin (3 mm), or simvastatin (3 μm)) for 2, 4 or 6 h followed by reacting with FITC‐conjugated annexin V for the detection of initial apoptosis signal (flip‐flop). Various statin‐treated myoblasts were significantly stained with FITC‐annexin V at 6 h, whereas they were not detected at 2 h. Moreover, immunoblot analysis indicated that when the cells were treated with cerivastatin (3 μm), membrane‐associated Ras protein was activated and detached until 6 h, resulting in cell death through the consequent activation of caspase‐8. On the other hand, since cytosolic Ras activation did not activate, there is still an unknown mechanism in statin‐related Ras depletion. In conclusion, statin‐induced apoptosis in muscular tissue was directly initiated by the farnesyl‐anchored Ras protein depletion from cell membrane with subsequent apoptosis.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>16259781</pmid><doi>10.1211/jpp.57.11.0014</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Apoptosis Atorvastatin Calcium Caspase 8 - metabolism Cell Line Fatty Acids, Monounsaturated - pharmacology Flow Cytometry Heptanoic Acids - pharmacology Hydroxymethylglutaryl-CoA Reductase Inhibitors Indoles - pharmacology Membrane Lipids - metabolism Microscopy, Fluorescence Myoblasts, Skeletal - drug effects Myoblasts, Skeletal - metabolism Myoblasts, Skeletal - ultrastructure Protein Prenylation Pyridines - pharmacology Pyrroles - pharmacology ras Proteins - metabolism Rats rho GTP-Binding Proteins - metabolism Signal Transduction - drug effects |
title | Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein |
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