Abstract
BackgroundIn our model of congenital heart disease (CHD) with increased pulmonary blood flow (Shunt), we have recently shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction and decreased eNOS/Hsp90 interactions that contribute to eNOS uncoupling, increased superoxide levels, and decreased bioavailable NO. Thus, 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 following delivery, lambs received daily treatment with oral L-carnitine or its vehicle.ResultsL-carnitine-treated lambs had decreased levels of acyl carnitine, and a reduced acyl carnitine: free carnitine ratio compared to 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, NOx levels, and a significant decrease in eNOS-derived superoxide. Further, acetylcholine significantly decreased left pulmonary vascular resistance (PVR) only in L-carnitine-treated lambs.ConclusionL-carnitine therapy may improve the endothelial dysfunction noted in children with CHD, and has important clinical implications that warrant further investigation.
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