title: Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors.
abstract: To determine a potential role for the renin-angiotensin system in the growth of human pulmonary artery (PA) smooth muscle, we studied the localization of angiotensin (ANG) II-receptor subtypes by autoradiography in sections of human PA and in cultured PA smooth muscle cells (PASMCs) and examined the growth responses to ANG II in vitro. Specific 125I-labeled [Sar1,Ile8]ANG II binding was demonstrated within the pulmonary arterial media, but binding to cultured cells varied between isolates. Binding in tissues and cells was inhibited by the ANG II type 1 (AT1) receptor antagonist losartan but not by the type 2 (AT2) receptor antagonist PD-123319. Microautoradiographic studies indicated that cultured PASMCs exhibit heterogeneity with regard to ANG II binding sites. Addition of ANG II to serum-deprived PASMCs, exhibiting a relatively high level of 125I-[Sar1,Ile8]ANG II binding, led to a dose-dependent stimulation of DNA synthesis at 24 h and protein synthesis at 48 h. ANG II led to an increase in cell size without an increase in cell number. These effects were inhibited by losartan but not by PD-123319. In addition, ANG II led to rapid activation of mitogen-activated protein kinase (MAPK), and ANG II-stimulated DNA synthesis was inhibited by the specific inhibitor of MAPK PD-98059. We conclude that the AT1 receptor is expressed by human PASMCs in vivo and in vitro and is coupled to activation of MAPK and increased DNA and protein synthesis in vitro. These results are consistent with the hypothesis that ANG II may be involved in human pulmonary vascular remodeling.
authors.affiliation: Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom. nmorrell@rpms.ac.uk
authors.forename: N W
authors.initials: NW
authors.lastname: Morrell
authors.forename: P D
authors.initials: PD
authors.lastname: Upton
authors.forename: S
authors.initials: S
authors.lastname: Kotecha
authors.forename: A
authors.initials: A
authors.lastname: Huntley
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: J M
authors.initials: JM
authors.lastname: Polak
authors.forename: J
authors.initials: J
authors.lastname: Wharton
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases