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 Raff, Kon Xoinis, Gohkan Kalkan, Sohrab Fratz, Jeffrey R. Fineman, Stephen Matthew Black

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 1 2013

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Carnitine
Lung
Nitric Oxide Synthase Type III
Acetylcarnitine
Transferases
Superoxides
Nitric Oxide
HSP90 Heat-Shock Proteins
Congenital Heart Defects
Pyruvic Acid
Vascular Resistance
Acetylcholine
Lactic Acid
Proteins
Homeostasis
Therapeutics
Transplants
Enzymes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow. / Sharma, Shruti; Aramburo, Angela; Rafikov, Ruslan; Sun, Xutong; Kumar, Sanjiv; Oishi, Peter E.; Datar, Sanjeev A.; Raff, Gary; Xoinis, Kon; Kalkan, Gohkan; Fratz, Sohrab; Fineman, Jeffrey R.; Black, Stephen Matthew.

In: Pediatric Research, Vol. 74, No. 1, 01.07.2013, p. 39-47.

Research output: Contribution to journalArticle

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, SM 2013, 'L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow', Pediatric Research, vol. 74, no. 1, pp. 39-47. https://doi.org/10.1038/pr.2013.71
Sharma, Shruti ; Aramburo, Angela ; Rafikov, Ruslan ; Sun, Xutong ; Kumar, Sanjiv ; Oishi, Peter E. ; Datar, Sanjeev A. ; Raff, Gary ; Xoinis, Kon ; Kalkan, Gohkan ; Fratz, Sohrab ; Fineman, Jeffrey R. ; Black, Stephen Matthew. / L-Carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow. In: Pediatric Research. 2013 ; Vol. 74, No. 1. pp. 39-47.
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AU - Rafikov, Ruslan

AU - Sun, Xutong

AU - Kumar, Sanjiv

AU - Oishi, Peter E.

AU - Datar, Sanjeev A.

AU - Raff, Gary

AU - Xoinis, Kon

AU - Kalkan, Gohkan

AU - Fratz, Sohrab

AU - Fineman, Jeffrey R.

AU - Black, Stephen Matthew

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AB - 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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