L-Carnitine attenuates angiotensin II-induced proliferation of cardiac fibroblasts: Role of NADPH oxidase inhibition and decreased sphingosine-1-phosphate generation

Hung Hsin Chao, Cheng Hsien Chen, Ju Chi Liu, Jia Wei Lin, Kar Lok Wong, Tzu-Hurng Cheng

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Abstract

The heart is unable to synthesize l-carnitine and is strictly dependent on the l-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of l-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of l-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with l-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by l-carnitine. l-Carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, l-carnitine increased prostacyclin (PGI2) generation in cardiac fibroblasts. siRNA transfection of PGI2 synthase significantly reduced l-carnitine-induced PGI2 and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI2 receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR?) and delta , revealed that siRNA-mediated blockage of PPAR? considerably reduced the anti-proliferation effect of l-carnitine. In summary, these results suggest that l-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI2 and PPAR?-signaling pathways.

Original languageEnglish
Pages (from-to)580-588
Number of pages9
JournalJournal of Nutritional Biochemistry
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 2010

Fingerprint

Carnitine
NADPH Oxidase
Fibroblasts
Angiotensin II
Epoprostenol
PPAR alpha
Small Interfering RNA
sphingosine 1-phosphate
Epoprostenol Receptors
PPAR delta
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Transcription Factor AP-1
Cell proliferation
Endothelin-1
Immunoprecipitation
Transfection
Rats
Reactive Oxygen Species
Blood

Keywords

  • Angiotensin II
  • Cardiac fibroblasts
  • L-carnitine
  • NADPH oxidase
  • Prostacyclin
  • Sphingosine-1-phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics
  • Medicine(all)

Cite this

@article{82449b136dc34dcaa8979b8d36f50e5e,
title = "L-Carnitine attenuates angiotensin II-induced proliferation of cardiac fibroblasts: Role of NADPH oxidase inhibition and decreased sphingosine-1-phosphate generation",
abstract = "The heart is unable to synthesize l-carnitine and is strictly dependent on the l-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of l-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of l-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with l-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by l-carnitine. l-Carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, l-carnitine increased prostacyclin (PGI2) generation in cardiac fibroblasts. siRNA transfection of PGI2 synthase significantly reduced l-carnitine-induced PGI2 and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI2 receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR?) and delta , revealed that siRNA-mediated blockage of PPAR? considerably reduced the anti-proliferation effect of l-carnitine. In summary, these results suggest that l-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI2 and PPAR?-signaling pathways.",
keywords = "Angiotensin II, Cardiac fibroblasts, L-carnitine, NADPH oxidase, Prostacyclin, Sphingosine-1-phosphate",
author = "Chao, {Hung Hsin} and Chen, {Cheng Hsien} and Liu, {Ju Chi} and Lin, {Jia Wei} and Wong, {Kar Lok} and Tzu-Hurng Cheng",
year = "2010",
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language = "English",
volume = "21",
pages = "580--588",
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T1 - L-Carnitine attenuates angiotensin II-induced proliferation of cardiac fibroblasts

T2 - Role of NADPH oxidase inhibition and decreased sphingosine-1-phosphate generation

AU - Chao, Hung Hsin

AU - Chen, Cheng Hsien

AU - Liu, Ju Chi

AU - Lin, Jia Wei

AU - Wong, Kar Lok

AU - Cheng, Tzu-Hurng

PY - 2010/7

Y1 - 2010/7

N2 - The heart is unable to synthesize l-carnitine and is strictly dependent on the l-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of l-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of l-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with l-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by l-carnitine. l-Carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, l-carnitine increased prostacyclin (PGI2) generation in cardiac fibroblasts. siRNA transfection of PGI2 synthase significantly reduced l-carnitine-induced PGI2 and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI2 receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR?) and delta , revealed that siRNA-mediated blockage of PPAR? considerably reduced the anti-proliferation effect of l-carnitine. In summary, these results suggest that l-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI2 and PPAR?-signaling pathways.

AB - The heart is unable to synthesize l-carnitine and is strictly dependent on the l-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of l-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of l-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with l-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by l-carnitine. l-Carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, l-carnitine increased prostacyclin (PGI2) generation in cardiac fibroblasts. siRNA transfection of PGI2 synthase significantly reduced l-carnitine-induced PGI2 and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI2 receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR?) and delta , revealed that siRNA-mediated blockage of PPAR? considerably reduced the anti-proliferation effect of l-carnitine. In summary, these results suggest that l-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI2 and PPAR?-signaling pathways.

KW - Angiotensin II

KW - Cardiac fibroblasts

KW - L-carnitine

KW - NADPH oxidase

KW - Prostacyclin

KW - Sphingosine-1-phosphate

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