TY - JOUR T1 - The Vascular Smooth Muscle Type I Angiotensin II Receptor mRNA Is Destabilized by Cyclic AMP-Elevating Agents JF - Molecular Pharmacology JO - Mol Pharmacol SP - 781 LP - 787 DO - 10.1124/mol.52.5.781 VL - 52 IS - 5 AU - Xiaofei Wang AU - Georg Nickenig AU - T. J. Murphy Y1 - 1997/11/01 UR - http://molpharm.aspetjournals.org/content/52/5/781.abstract N2 - Although processes involved in mRNA degradation play a significant role in dictating steady state mRNA levels, the influence of cell surface signaling on mRNA stability control is understood incompletely. In this study, the effects of cAMP-elevating agents on type I angiotensin II receptor (AT1-R) mRNA levels were assessed in cultured rat aortic vascular smooth muscle cells (VSMCs). AT1-R mRNA levels are rapidly reduced by forskolin treatment, in which the maximal effect yields an 80% reduction in AT1-R mRNA levels after 6 hr of treatment. The rate of AT1-R mRNA decay in response to forskolin is greater than its apparent intrinsic decay, as assessed in the presence of the transcriptional inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole, suggesting forskolin treatment destabilizes the AT1-R mRNA. Nuclear run-on analysis indicates forskolin treatment does not affect transcription of the AT1-R gene in VSMCs, implying induced AT1-R mRNA destabilization accounts for the entire effect of forskolin in decreasing AT1-R mRNA levels. Dose-effect studies that assessed AT1-R mRNA levels and cAMP production were conducted using forskolin and the β-adrenergic receptor agonist isoproterenol as agonists. Isoproterenol is almost 3 orders of magnitude more potent at eliciting the reduction in AT1-receptor mRNA levels than it is at stimulating cAMP production. Similarly, forskolin elicits reductions in AT1-R mRNA, which occur at concentrations that fail to elicit a detectable production of cAMP. However, protein kinase A activity is stimulated maximally by isoproterenol and forskolin concentrations that do not stimulate detectable cAMP production. These data provide evidence that the mechanism for down-regulation of AT1-R mRNA levels by cAMP-elevating agents in VSMCs occurs via a PKA-regulated mRNA destabilization pathway. ER -