L-carnitine therapy improves endothelial function in a lamb model of increased pulmonary blood flow

Resumo

Congenital heart disease (CHD) with increased pulmonary blood flow (PBF) results in a progressive pulmonary vascular endothelial dysfunction that is partly dependent on decreased nitric oxide (NO) signaling. In a lamb model of CHD with increased PBF, we have previously shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction that contributes to eNOS uncoupling and decreased bioavailable NO. This study aims to test the hypothesis that Lcarnitine therapy would maintain carnitine homeostasis, mitochondrial function and NO signaling in our lamb model of increased PBF. Methods: 13 fetal lambs underwent in-utero placement of an aorto-pulmonary graft (shunt). Immediately following spontaneous delivery, lambs received daily treatment with oral L-carnitine (n=7; 100 mg/kg/day) or its vehicle (n=6). An additional group of eleven lambs with normal PBF served as controls. Results: At 4-weeks of age, L-carnitine-treated shunt lambs had decreased levels of acylcarnitine and a reduced acylcarnitine/free carnitine ratio compared to vehicle-treated shunt lambs. These changes correlated with increased carnitine acetyl-transferase (CrAT) protein and enzyme activity, as well as decreased levels of nitrated CrAT. The lactate/pyruvate ratio was also decreased in L-carnitine-treated shunt lambs. Furthermore, Hsp70 protein levels were significantly decreased in L-carnitine-treated shunt lambs, which correlated with a significant increase in eNOS/Hsp90 interactions, NOS activity, and NOx levels, as well as with a significant decrease in eNOS derived superoxide. Further, acetylcholine significantly decreased left pulmonary vascular resistance (PVR) only in L-carnitine-treated shunt lambs. Conclusions: Early L-carnitine therapy may improve and/or attenuate the decline in endothelial function noted in children with CHD associated with pulmonary overflow, and thus has potentially important clinical implications that warrant further investigation.