title: L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow.
abstract: BACKGROUND
  In our model of a congenital heart defect (CHD) with increased pulmonary blood flow (PBF; shunt), we have recently shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction and decreased endothelial nitric oxide synthase (eNOS)/heat shock protein (Hsp)90 interactions that contribute to eNOS uncoupling, increased superoxide levels, and decreased bioavailable nitric oxide (NO). Therefore, we undertook this study to test the hypothesis that L-carnitine therapy would maintain mitochondrial function and NO signaling.
  
  
  METHODS
  Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft. Immediately after delivery, lambs received daily treatment with oral L-carnitine or its vehicle.
  
  
  RESULTS
  L-Carnitine-treated lambs had decreased levels of acylcarnitine and a reduced acylcarnitine:free carnitine ratio as compared with vehicle-treated shunt lambs. These changes correlated with increased carnitine acetyl transferase (CrAT) protein and enzyme activity and decreased levels of nitrated CrAT. The lactate:pyruvate ratio was also decreased in L-carnitine-treated lambs. Hsp70 protein levels were significantly decreased, and this correlated with increases in eNOS/Hsp90 interactions, NOS activity, and NOx levels, and a significant decrease in eNOS-derived superoxide. Furthermore, acetylcholine significantly decreased left pulmonary vascular resistance only in L-carnitine-treated lambs.
  
  
  CONCLUSIONS
  L-Carnitine therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation.
authors.affiliation: Pulmonary Vascular Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Angela
authors.initials: A
authors.lastname: Aramburo
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.forename: Xutong
authors.initials: X
authors.lastname: Sun
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
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: Kon
authors.initials: K
authors.lastname: Xoinis
authors.forename: Gohkan
authors.initials: G
authors.lastname: Kalkan
authors.forename: Sohrab
authors.initials: S
authors.lastname: Fratz
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D004716:Endometritis / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006706:Homeostasis; D008168:Lung / Q000098:blood supply*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012039:Regional Blood Flow; D012756:Sheep; D013481:Superoxides / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D002331:Carnitine