title: Endothelin-1 inhibits apoptosis of vascular smooth muscle cells induced by nitric oxide and serum deprivation via MAP kinase pathway.
abstract: Endothelin (ET)-1, an endothelium-derived vasoconstrictor and mitogen, acts as an antiapoptotic factor against serum deprivation-induced apoptosis of endothelial cells and fibroblasts but enhances apoptosis of some cancer cells. In the present study, we examined whether nitric oxide (NO) and ET-1 modulate apoptosis of rat vascular smooth muscle cells (VSMCs) via the mitogen-activated protein (MAP) kinase pathway. Both serum deprivation and NO donors (FK409 and SNAP) caused apoptosis of VSMCs, as demonstrated by TdT-mediated dUTP-biotin nick end-labeling, appearance of fragmented DNA, and induction of caspase-3 activity. ET-1 dose-dependently antagonized apoptosis induced by serum deprivation and NO donors. A selective ET(A) receptor antagonist (BQ123) and a nonselective ET(A/B) receptor antagonist (TAK044), but not a selective ET(B) receptor antagonist (BQ788), inhibited the antiapoptotic effect of ET-1, indicating that the antiapoptotic effect of ET-1 is mediated via the ET(A) receptor. ET-1 activated MAP kinase, whose effect was inhibited by FK409. Transfection with an unphosphorylated wild-type MAP kinase kinase-1 (MAPKK-1) or its constitutively activated mutant protected VSMCs against apoptosis induced by serum deprivation and NO donors. Inhibition of MAP kinase activity with PD98059, a specific inhibitor of MAPKK-1, or by transfection of a dominant-negative MAPKK-1 mutant antagonized the antiapoptotic effect of ET-1, suggesting the involvement of MAP kinase in the antiapoptotic effect. The potent inhibitory effect of ET-1 on apoptosis of VSMCs induced by serum deprivation and NO suggests that the counterbalance between the 2 endothelium-derived factors contributes to the process of vascular remodeling by determining VSMC survival and death, respectively, via a common MAP kinase pathway.
authors.affiliation: Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan. mshichiri.med2@med.tmd.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Shichiri
authors.forename: M
authors.initials: M
authors.lastname: Yokokura
authors.forename: F
authors.initials: F
authors.lastname: Marumo
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D000818:Animals; D001011:Aorta; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016895:Culture Media, Serum-Free; D053938:DNA Fragmentation; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009569:Nitric Oxide / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats
chemical_list: D016895:Culture Media, Serum-Free; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C088196:TAK 044; D009569:Nitric Oxide; C086539:BQ 788; D020928:Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C072247:cyclo(Trp-Asp-Pro-Val-Leu)