PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow
Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carri...
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| Veröffentlicht in: | PloS one 2012-09, Vol.7 (9), p.e41555 |
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| creator | Sharma, Shruti Sun, Xutong Rafikov, Ruslan Kumar, Sanjiv Hou, Yali Oishi, Peter E Datar, Sanjeev A Raff, Gary Fineman, Jeffrey R Black, Stephen M |
| description | Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.
siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.
Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow. |
| doi_str_mv | 10.1371/journal.pone.0041555 |
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siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.
Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0041555</identifier><identifier>PMID: 22962578</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetyltransferase ; Animals ; Animals, Newborn ; ATP ; Biology ; Blood ; Blood flow ; Carnitine ; Carnitine - metabolism ; Carnitine O-Acetyltransferase - genetics ; Carnitine O-Acetyltransferase - metabolism ; Carnitine O-Palmitoyltransferase - genetics ; Carnitine O-Palmitoyltransferase - metabolism ; Children ; Diabetes ; Gene expression ; Gene Expression Regulation - drug effects ; Health sciences ; Homeostasis ; HSP90 Heat-Shock Proteins - genetics ; HSP90 Heat-Shock Proteins - metabolism ; Hsp90 protein ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Lung - drug effects ; Lung - metabolism ; Lung - pathology ; Lung - surgery ; Metabolism ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Models, Animal ; Nitric oxide ; Nitric Oxide - metabolism ; Nitric Oxide Synthase Type III - genetics ; Nitric Oxide Synthase Type III - metabolism ; Oxidative Stress - drug effects ; Pediatrics ; Peroxisome proliferator-activated receptors ; Phosphorylation ; PPAR gamma - antagonists & inhibitors ; PPAR gamma - genetics ; PPAR gamma - metabolism ; Proteins ; Pulmonary Artery - drug effects ; Pulmonary Artery - metabolism ; Pulmonary Artery - pathology ; Pulmonary Artery - surgery ; Pulmonary Circulation - drug effects ; Pulmonary hypertension ; Reduction ; Regulatory proteins ; Rodents ; Rosiglitazone ; Shear stress ; Sheep, Domestic ; Signal Transduction - drug effects ; Signaling ; siRNA ; Superoxides - metabolism ; Thiazolidinediones - pharmacology ; Vasodilator Agents - pharmacology</subject><ispartof>PloS one, 2012-09, Vol.7 (9), p.e41555</ispartof><rights>Sharma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Sharma et al 2012 Sharma et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a014edec34618789aacd2e09d01489fedad7aed6fcb12e34c6a22d8bd59997563</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433474/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433474/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22962578$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sharma, Shruti</creatorcontrib><creatorcontrib>Sun, Xutong</creatorcontrib><creatorcontrib>Rafikov, Ruslan</creatorcontrib><creatorcontrib>Kumar, Sanjiv</creatorcontrib><creatorcontrib>Hou, Yali</creatorcontrib><creatorcontrib>Oishi, Peter E</creatorcontrib><creatorcontrib>Datar, Sanjeev A</creatorcontrib><creatorcontrib>Raff, Gary</creatorcontrib><creatorcontrib>Fineman, Jeffrey R</creatorcontrib><creatorcontrib>Black, Stephen M</creatorcontrib><title>PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.
siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.
Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.</description><subject>Acetyltransferase</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>ATP</subject><subject>Biology</subject><subject>Blood</subject><subject>Blood flow</subject><subject>Carnitine</subject><subject>Carnitine - metabolism</subject><subject>Carnitine O-Acetyltransferase - genetics</subject><subject>Carnitine O-Acetyltransferase - metabolism</subject><subject>Carnitine O-Palmitoyltransferase - genetics</subject><subject>Carnitine O-Palmitoyltransferase - metabolism</subject><subject>Children</subject><subject>Diabetes</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Health sciences</subject><subject>Homeostasis</subject><subject>HSP90 Heat-Shock Proteins - genetics</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Hsp90 protein</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Lung - drug effects</subject><subject>Lung - metabolism</subject><subject>Lung - pathology</subject><subject>Lung - surgery</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Models, Animal</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase Type III - genetics</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>Oxidative Stress - drug effects</subject><subject>Pediatrics</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Phosphorylation</subject><subject>PPAR gamma - antagonists & inhibitors</subject><subject>PPAR gamma - genetics</subject><subject>PPAR gamma - metabolism</subject><subject>Proteins</subject><subject>Pulmonary Artery - drug effects</subject><subject>Pulmonary Artery - metabolism</subject><subject>Pulmonary Artery - pathology</subject><subject>Pulmonary Artery - surgery</subject><subject>Pulmonary Circulation - drug effects</subject><subject>Pulmonary hypertension</subject><subject>Reduction</subject><subject>Regulatory proteins</subject><subject>Rodents</subject><subject>Rosiglitazone</subject><subject>Shear stress</subject><subject>Sheep, Domestic</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Superoxides - metabolism</subject><subject>Thiazolidinediones - pharmacology</subject><subject>Vasodilator Agents - pharmacology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uttu1DAUjBCIlsIfILDEcxbf4sQvSFXFpVIlKgTP1ol9suuVYy92AuK7-A--iZRNq_aBJ1tzZuaMjqaqXjK6YaJlb_dpzhHC5pAibiiVrGmaR9Up04LXilPx-N7_pHpWyp7SRnRKPa1OONeKN213Wk3X1-df6j-_ScbtHGDCQizk6CcfkezSiKlMUHwhEB0Z_ZTsLkWXPQQyzNFOPkXiIwESYOzJmBwGkoYFshmhoCOHOYwpQv5F-pCSI0NIP59XTwYIBV-s71n17cP7rxef6qvPHy8vzq9q23A11UCZRIdWSMW6ttMA1nGk2i14pwd04FpApwbbM45CWgWcu653jda6bZQ4q14ffQ8hFbMerBgmuGqkXCgL4_LIcAn25pD9uCQ1Cbz5B6S8NZAnbwMaaDVqQYG2TS_bnsNySqYYd70S3Gm6eL1bt839iM5inDKEB6YPJ9HvzDb9MEIKIVu5GLxZDXL6PmOZ_hNZHlk2p1IyDncbGDU3zbhVmZtmmLUZi-zV_XR3otsqiL9KiLot</recordid><startdate>20120904</startdate><enddate>20120904</enddate><creator>Sharma, Shruti</creator><creator>Sun, Xutong</creator><creator>Rafikov, Ruslan</creator><creator>Kumar, Sanjiv</creator><creator>Hou, Yali</creator><creator>Oishi, Peter E</creator><creator>Datar, Sanjeev A</creator><creator>Raff, Gary</creator><creator>Fineman, Jeffrey R</creator><creator>Black, Stephen M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120904</creationdate><title>PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow</title><author>Sharma, Shruti ; Sun, Xutong ; Rafikov, Ruslan ; Kumar, Sanjiv ; Hou, Yali ; Oishi, Peter E ; Datar, Sanjeev A ; Raff, Gary ; Fineman, Jeffrey R ; Black, Stephen M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-a014edec34618789aacd2e09d01489fedad7aed6fcb12e34c6a22d8bd59997563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Acetyltransferase</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>ATP</topic><topic>Biology</topic><topic>Blood</topic><topic>Blood flow</topic><topic>Carnitine</topic><topic>Carnitine - metabolism</topic><topic>Carnitine O-Acetyltransferase - genetics</topic><topic>Carnitine O-Acetyltransferase - metabolism</topic><topic>Carnitine O-Palmitoyltransferase - genetics</topic><topic>Carnitine O-Palmitoyltransferase - metabolism</topic><topic>Children</topic><topic>Diabetes</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Health sciences</topic><topic>Homeostasis</topic><topic>HSP90 Heat-Shock Proteins - genetics</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Hsp90 protein</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Lung - drug effects</topic><topic>Lung - metabolism</topic><topic>Lung - pathology</topic><topic>Lung - surgery</topic><topic>Metabolism</topic><topic>Mitochondria</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Models, Animal</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase Type III - 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Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.
siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.
Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22962578</pmid><doi>10.1371/journal.pone.0041555</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1326544975 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acetyltransferase Animals Animals, Newborn ATP Biology Blood Blood flow Carnitine Carnitine - metabolism Carnitine O-Acetyltransferase - genetics Carnitine O-Acetyltransferase - metabolism Carnitine O-Palmitoyltransferase - genetics Carnitine O-Palmitoyltransferase - metabolism Children Diabetes Gene expression Gene Expression Regulation - drug effects Health sciences Homeostasis HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Hsp90 protein Isoenzymes - genetics Isoenzymes - metabolism Lung - drug effects Lung - metabolism Lung - pathology Lung - surgery Metabolism Mitochondria Mitochondria - drug effects Mitochondria - metabolism Models, Animal Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type III - genetics Nitric Oxide Synthase Type III - metabolism Oxidative Stress - drug effects Pediatrics Peroxisome proliferator-activated receptors Phosphorylation PPAR gamma - antagonists & inhibitors PPAR gamma - genetics PPAR gamma - metabolism Proteins Pulmonary Artery - drug effects Pulmonary Artery - metabolism Pulmonary Artery - pathology Pulmonary Artery - surgery Pulmonary Circulation - drug effects Pulmonary hypertension Reduction Regulatory proteins Rodents Rosiglitazone Shear stress Sheep, Domestic Signal Transduction - drug effects Signaling siRNA Superoxides - metabolism Thiazolidinediones - pharmacology Vasodilator Agents - pharmacology |
| title | PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T22%3A04%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=PPAR-%CE%B3%20regulates%20carnitine%20homeostasis%20and%20mitochondrial%20function%20in%20a%20lamb%20model%20of%20increased%20pulmonary%20blood%20flow&rft.jtitle=PloS%20one&rft.au=Sharma,%20Shruti&rft.date=2012-09-04&rft.volume=7&rft.issue=9&rft.spage=e41555&rft.pages=e41555-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0041555&rft_dat=%3Cproquest_plos_%3E2943642701%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1326544975&rft_id=info:pmid/22962578&rft_doaj_id=oai_doaj_org_article_a79e930a075b47b2a8661612db632d90&rfr_iscdi=true |