L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow

Shruti Sharma, Angela Aramburo, Ruslan Rafikov, Xutong Sun, Sanjiv Kumar, Peter E. Oishi, Sanjeev A. Datar, Gary W Raff, Kon Xoinis, Gohkan Kalkan, Sohrab Fratz, Jeffrey R. Fineman, Stephen M. Black

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)39-47
Number of pages9
JournalPediatric Research
Volume74
Issue number1
DOIs
StatePublished - Jul 2013

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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    Sharma, S., Aramburo, A., Rafikov, R., Sun, X., Kumar, S., Oishi, P. E., Datar, S. A., Raff, G. W., Xoinis, K., Kalkan, G., Fratz, S., Fineman, J. R., & Black, S. M. (2013). L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow. Pediatric Research, 74(1), 39-47. https://doi.org/10.1038/pr.2013.71