PPAR-c Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

Hdl Handle:
http://hdl.handle.net/10675.2/825
Title:
PPAR-c Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow
Authors:
Sharma, Shruti; Sun, Xutong; Rafikov, Ruslan; Kumar, Sanjiv; Hou, Yali; Oishi, Peter E.; Datar, Sanjeev A.; Raff, Gary; Fineman, Jeffrey R.; Black, Stephen M.
Abstract:
Objective: 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-c expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-c signaling and carnitine dysfunction, and whether the PPAR-c agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.; Methods and Results: siRNA-mediated PPAR-c 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.; Conclusion: Our study indicates that PPAR-c 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-c regulates NO signaling through Hsp90. Thus, PPAR-c agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.
Citation:
PLoS One. 2012 Sep 4; 7(9):e41555
Issue Date:
4-Sep-2012
URI:
http://hdl.handle.net/10675.2/825
DOI:
10.1371/journal.pone.0041555
PubMed ID:
22962578
PubMed Central ID:
PMC3433474
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Vascular Biology Center: Faculty Research and Publication

Full metadata record

DC FieldValue Language
dc.contributor.authorSharma, Shrutien_US
dc.contributor.authorSun, Xutongen_US
dc.contributor.authorRafikov, Ruslanen_US
dc.contributor.authorKumar, Sanjiven_US
dc.contributor.authorHou, Yalien_US
dc.contributor.authorOishi, Peter E.en_US
dc.contributor.authorDatar, Sanjeev A.en_US
dc.contributor.authorRaff, Garyen_US
dc.contributor.authorFineman, Jeffrey R.en_US
dc.contributor.authorBlack, Stephen M.en_US
dc.date.accessioned2012-10-26T20:35:12Z-
dc.date.available2012-10-26T20:35:12Z-
dc.date.issued2012-09-4en_US
dc.identifier.citationPLoS One. 2012 Sep 4; 7(9):e41555en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22962578en_US
dc.identifier.doi10.1371/journal.pone.0041555en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/825-
dc.description.abstractObjective: 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-c expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-c signaling and carnitine dysfunction, and whether the PPAR-c agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.en_US
dc.description.abstractMethods and Results: siRNA-mediated PPAR-c 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.en_US
dc.description.abstractConclusion: Our study indicates that PPAR-c 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-c regulates NO signaling through Hsp90. Thus, PPAR-c agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectNeurochemistryen_US
dc.subjectNeurochemicalsen_US
dc.subjectNitric Oxideen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectMechanisms of Signal Transductionen_US
dc.subjectSecond Messenger Systemen_US
dc.subjectSignaling in Cellular Processesen_US
dc.subjectRedox Signalingen_US
dc.subjectSignaling Cascadesen_US
dc.subjectSignaling in Selected Disciplinesen_US
dc.subjectCellular Stress Responsesen_US
dc.subjectGene Expressionen_US
dc.titlePPAR-c Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flowen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3433474en_US
dc.contributor.corporatenameVascular Biology Center-

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