Propofol depresses angiotensin II-induced cell proliferation in rat cardiac fibroblasts.
BACKGROUND
Propofol may have beneficial effects on the prevention of angiotensin II (Ang II)-induced cardiac fibroblast proliferation via its antioxidative properties. The authors hypothesized that propofol may alter Ang II-induced cell proliferation and aimed to identify the putative underlying signaling pathways in rat cardiac fibroblasts.


METHODS
Cultured rat cardiac fibroblasts were pretreated with propofol then stimulated with Ang II; cell proliferation and endothelin-1 gene expression were examined. The effect of propofol on Ang II-induced nicotinamide adenine dinucleotide phosphate-oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, and activator protein 1-mediated reporter activity were also examined. The effect of propofol on nitric oxide production and protein kinase B and endothelial nitric oxide synthase phosphorylations were also tested to elucidate the intracellular mechanism of propofol in proliferation.


RESULTS
Ang II (100 nm) increased cell proliferation and endothelin-1 expression, which were partially inhibited by propofol (10 or 30 microm). Propofol also inhibited Ang II-increased nicotinamide adenine dinucleotide phosphate-oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, and activator protein 1-mediated reporter activity. Propofol was also found to increase nitric oxide generation and protein kinase B and nitric oxide synthase phosphorylations. Nitric oxide synthase inhibitor (N-nitro-L-arginine methylester) and the short interfering RNA transfection for protein kinase B or endothelial nitric oxide synthase markedly attenuated the inhibitory effect of propofol on Ang II-induced cell proliferation.


CONCLUSIONS
The authors' results suggest that propofol prevents cardiac fibroblast proliferation by interfering with the generation of reactive oxygen species and involves the activation of the protein kinase B-endothelial nitric oxide synthase-nitric oxide pathway.
Cheng
Tzu-Hurng
TH
Department of Biological Science and Technology, College of Life Sciences, China Medical University, China.
Leung
Yuk-Man
YM
Cheung
Chi-Wai
CW
Chen
Cheng-Hsien
CH
Chen
Yen-Ling
YL
Wong
Kar-Lok
KL
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects*; D005452:Fluoresceins; D032383:Myocytes, Cardiac / Q000187:drug effects*; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D015742:Propofol / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
D018686:Anesthetics, Intravenous; D000963:Antimetabolites; D018076:DNA, Complementary; D005452:Fluoresceins; D009566:Nitrates; D009573:Nitrites; C065013:2',7'-dichlorodihydrofluorescein; D013481:Superoxides; D000804:Angiotensin II; D012313:RNA; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D001973:Bromodeoxyuridine; D015742:Propofol