title: PPAR-γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow.
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-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Vascular Biology Center, Georgia Health Sciences University, Augusta, Georgia, United States of America.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Xutong
authors.initials: X
authors.lastname: Sun
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.forename: Yali
authors.initials: Y
authors.lastname: Hou
authors.forename: Peter E
authors.initials: PE
authors.lastname: Oishi
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Datar
authors.forename: Gary
authors.initials: G
authors.lastname: Raff
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002331:Carnitine / Q000378:metabolism*; D002332:Carnitine O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011652:Pulmonary Circulation / Q000187:drug effects; D000077154:Rosiglitazone; D034561:Sheep, Domestic; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007527:Isoenzymes; D047495:PPAR gamma; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D002334:Carnitine O-Palmitoyltransferase; D002332:Carnitine O-Acetyltransferase; D002331:Carnitine