Cilostazol enhances IL-1beta-induced NO production and apoptosis in rat vascular smooth muscle via PKA-dependent pathway.
Interleukin-1beta (IL-1beta) stimulates nitric oxide (NO) production and induces apoptosis in several tissues. Cilostazol is a Type 3 phosphodiesterase inhibitor. We investigated whether cilostazol affects IL-1beta-induced NO production and apoptosis in rat vascular smooth muscle cells. Cilostazol (100 nM-10 microM) potentiated NO production triggered by IL-1beta. The mRNA and protein expression of inducible NO synthase was also upregulated by cilostazol. KT5720, an inhibitor of protein kinase A, and N(G)-monomethyl-L-arginine, an inhibitor of NO synthase, abrogated cilostazol-enhanced IL-1beta-stimulated NO production and apoptosis. These results shows that cilostazol potentiates IL-1beta-induced NO production via PKA-pathway and thereafter augments apoptosis via NO-dependent pathway.
Ito
Chiharu
C
Department of Nephrology, Jichi Medical School, Yakushiji 3311-1, Minamikawachi, 329-0498, Tochigi, Japan.
Kusano
Eiji
E
Akimoto
Tetsu
T
Takeda
Shinichi
S
Sasaki
Nobuhiro
N
Umino
Tetsuo
T
Iimura
Osamu
O
Ando
Yasuhiro
Y
Asano
Yasushi
Y
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D000077407:Cilostazol; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000032:analysis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*
D007375:Interleukin-1; D009573:Nitrites; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D013777:Tetrazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D000077407:Cilostazol