Transcriptional suppression of rat angiotensin AT1a receptor gene expression by interferon-gamma in vascular smooth muscle cells

Angiotensin (Ang) II stimulates proliferation of vascular smooth muscle cel ls (VSMC) via its specific receptor AT1 subtype, possibly leading to athero sclerosis in hypertension. On the other hand, a cytokine interferon (IFN)-g amma 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 regula tion in VSMC. A firefly luciferase expression vector driven by the rat AT1a receptor gene promoter (similar to 3.2 kb) was transfected into the cultur ed rat VSMC, and luciferase expression was determined to estimate the trans cription function of the AT1a receptor gene promoter. RT-PCR was also carri ed out to determine mRNA expression of AT1a receptor in VSMC. IFN-gamma tre atment decreased AT1a receptor mRNA expression as well as luciferase expres sion in a dose-dependent manner. The analysis with deletion DNA fragments s howed that the IFN-responsive element was located between -987 and -331 pos itions, 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 I FN-gamma can inhibit AT1 receptor expression at gene transcription level, a nd that the transcription suppression is dependent on MAP kinase and Jak-2. Inhibition of AT1a receptor expression may possibly be implicated in the a nti-atherosclerotic action of IFN-gamma in VSMC. (C) 1999 Academic Press.