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L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow Sharma S; Aramburo A; Rafikov R; Sun X; Kumar S; Oishi PE; Datar SA; Raff G; Xoinis K; Kalkan G; Fratz S; Fineman JR; Black SMPediatr Res 2013[Jul]; 74 (1): 39-47BACKGROUND: 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.|Animals[MESH]|Carnitine/*pharmacology[MESH]|Endometritis/*physiopathology[MESH]|Endothelium, Vascular/*drug effects/physiopathology[MESH]|Female[MESH]|HSP90 Heat-Shock Proteins/metabolism[MESH]|Homeostasis[MESH]|Lung/*blood supply[MESH]|Mitochondria/drug effects/physiology[MESH]|Nitric Oxide Synthase Type III/metabolism[MESH]|Nitric Oxide/metabolism[MESH]|Regional Blood Flow[MESH]|Sheep[MESH]|Superoxides/metabolism[MESH] |
