• Shruti Sharma, Angela Aramburo, Ruslan Rafikov, Xutong Sun, Sanjiv Kumar, Peter E Oishi, Sanjeev A Datar, Gary Raff, Kon Xoinis, Gohkan Kalkan, Sohrab Fratz, Jeffrey R Fineman, and Stephen M Black.
• Pulmonary Vascular Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
• Pediatr. Res. 2013 Jul 1; 74 (1): 39-47.

BackgroundIn 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.MethodsThirteen fetal lambs underwent in utero placement of an aortopulmonary graft. Immediately after delivery, lambs received daily treatment with oral L-carnitine or its vehicle.ResultsL-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.ConclusionL-Carnitine therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation.

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