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.
Conclusion:
L-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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The authors thank Sridevi Dasarathy, Johnny Wright, Michael Johengen, and Cynthia Harmon for excellent technical assistance.
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Sharma, S., Aramburo, A., Rafikov, R. et al. L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow. Pediatr Res 74, 39–47 (2013). https://doi.org/10.1038/pr.2013.71
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DOI: https://doi.org/10.1038/pr.2013.71
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