title: Transcriptional suppression of rat angiotensin AT1a receptor gene expression by interferon-gamma in vascular smooth muscle cells.
abstract: Angiotensin (Ang) II stimulates proliferation of vascular smooth muscle cells (VSMC) via its specific receptor AT1 subtype, possibly leading to atherosclerosis in hypertension. On the other hand, a cytokine interferon (IFN)-gamma has been shown to have an anti-atherosclerotic effect. In the present study, we examined a possible role of IFN-gamma in AT1 receptor gene regulation in VSMC. A firefly luciferase expression vector driven by the rat AT1a receptor gene promoter ( approximately 3.2 kb) was transfected into the cultured rat VSMC, and luciferase expression was determined to estimate the transcription function of the AT1a receptor gene promoter. RT-PCR was also carried out to determine mRNA expression of AT1a receptor in VSMC. IFN-gamma treatment decreased AT1a receptor mRNA expression as well as luciferase expression in a dose-dependent manner. The analysis with deletion DNA fragments showed that the IFN-responsive element was located between -987 and -331 positions, where multiple GAS (gamma interferon activated site)-like elements were identified. The expression suppression was reversed by either a MAPKK inhibitor PD98059 or a Jak-2 inhibitor AG-490. These results suggest that IFN-gamma can inhibit AT1 receptor expression at gene transcription level, and that the transcription suppression is dependent on MAP kinase and Jak-2. Inhibition of AT1a receptor expression may possibly be implicated in the anti-atherosclerotic action of IFN-gamma in VSMC.
authors.affiliation: Second Department of Internal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Taniyama
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Sugawara
authors.forename: S
authors.initials: S
authors.lastname: Ito
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001161:Arteriosclerosis / Q000209:etiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases