L-Carnitine attenuates angiotensin II-induced proliferation of cardiac fibroblasts: role of NADPH oxidase inhibition and decreased sphingosine-1-phosphate generation.
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 (PGI(2)) generation in cardiac fibroblasts. siRNA transfection of PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI(2) receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPAR alpha) and delta, revealed that siRNA-mediated blockage of PPAR alpha 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 PGI(2) and PPAR alpha-signaling pathways.
Chao
Hung-Hsin
HH
Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
Chen
Cheng-Hsien
CH
Liu
Ju-Chi
JC
Lin
Jia-Wei
JW
Wong
Kar-Lok
KL
Cheng
Tzu-Hurng
TH
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology; D002331:Carnitine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D008246:Lysophospholipids / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D002316:Cardiotonic Agents; D019332:Endothelin-1; D008246:Lysophospholipids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000804:Angiotensin II; C060506:sphingosine 1-phosphate; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine; D002331:Carnitine