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

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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

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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

Cite this

Sharma, S., Aramburo, A., Rafikov, R., Sun, X., Kumar, S., Oishi, P. E., ... 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

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 W; Xoinis, Kon; Kalkan, Gohkan; Fratz, Sohrab; Fineman, Jeffrey R.; Black, Stephen M.

In: Pediatric Research, Vol. 74, No. 1, 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, GW, 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 W ; Xoinis, Kon ; Kalkan, Gohkan ; Fratz, Sohrab ; Fineman, Jeffrey R. ; Black, Stephen M. / 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 - Kumar, Sanjiv

AU - Oishi, Peter E.

AU - Datar, Sanjeev A.

AU - Raff, Gary W

AU - Xoinis, Kon

AU - Kalkan, Gohkan

AU - Fratz, Sohrab

AU - Fineman, Jeffrey R.

AU - Black, Stephen M.

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N2 - 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.

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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