Thromboxane prostanoid receptor in human airway smooth muscle cells: a relevant role in proliferation.
Thromboxane A(2) has been implicated as a mediator of bronchial hyperresponsiveness in asthma. Modulating agents are currently marketed in Japan and under clinical evaluation in the US, but full characterization of the thromboxane A(2) receptor and the signaling pathways that link it to the proliferative events taking place during airways structural remodeling has not been achieved. Here, we report that the presence of mRNA for both alpha and beta isoforms of the thromboxane A(2) receptor in smooth muscle cells from human bronchi correlates with protein expression evaluated by radioligand binding of the antagonist, SQ29,548 ([1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic-acid) (K(d)=3.4 nM+/-44%CV, coefficient of variation, B(max)=41 fmol/mg prot+/-38%CV). The receptor is functional, as the agonist, U46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxy-prosta-5Z,13E-dien-1-oic-acid), induced a concentration-dependent Ca(2+) transient (EC(50)=0.12 microM+/-27%CV). Furthermore, U46619 concentration dependently increased DNA synthesis and markedly potentiated the epidermal growth factor mitogenic effect. Both events were specifically inhibited by SQ29,548, independently from transactivation of the epidermal growth factor receptor and partially sensitive to pertussis toxin.
Capra
Valérie
V
Institut Féderatif de Recherche Circulation-Lariboisière, Hôpital Lariboisière, 75010 Paris, France. Valerie.Capra@unimi.it
Habib
Aïda
A
Accomazzo
Maria Rosa
MR
Ravasi
Saula
S
Citro
Simona
S
Levy-Toledano
Sylviane
S
Nicosia
Simonetta
S
Rovati
G Enrico
GE
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000502:physiology*
D044244:Receptors, Thromboxane A2, Prostaglandin H2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid