THE VASCULAR SMOOTH-MUSCLE TYPE-I ANGIOTENSIN-II RECEPTOR MESSENGER-RNA IS DESTABILIZED BY CYCLIC AMP-ELEVATING AGENTS

Although processes involved in mRNA degradation play a significant rol e in dictating steady state mRNA levers, the influence of cell surface signaling on mRNA stability control is understood incompletely. In th is study, the effects of cAMP-elevating agents on type I angiotensin I I receptor (AT(1)-R) mRNA levels were assessed in cultured rat aortic vascular smooth muscle cells (VSMCs), AT(1)-R mRNA levels are rapidly reduced by forskolin treatment, in which the maximal effect yields an 80% reduction in AT(1)-R mRNA levels after 6 hr of treatment. The rate of AT(1)-R mRNA decay in response to forskolin is greater than its ap parent intrinsic decay, as assessed in the presence of the transcripti onal inhibitor 5,6-dichloro-1-beta-D-ribofuranosylben- zimidazole, sug gesting forskolin treatment destabilizes the AT(1)-R mRNA. Nuclear run -on analysis indicates forskolin treatment does not affect transcripti on of the AT(1)-R gene in VSMCs, implying induced AT(1)-R mRNA destabi lization accounts for the entire effect of forskolin in decreasing AT( 1)-R mRNA levels. Dose-effect studies that assessed AT(1)-R mRNA level s and cAMP production were conducted using forskolin and the beta-adre nergic receptor agonist isoproterenol as agonists. Isoproterenol is al most 3 orders of magnitude more potent at eliciting the reduction in A T(1)-receptor mRNA levels than it is at stimulating cAMP production. S imilarly, forskolin elicits reductions in AT(1)-R mRNA, which occur at concentrations that fail to elicit a detectable production of cAMP. H owever, protein kinase A activity is stimulated maximally by isoproter enol and forskolin concentrations that do not stimulate detectable cAM P production. These data provide evidence that the mechanism for down- regulation of AT(1)-R mRNA levels by cAMP-elevating agents in VSMCs oc curs via a PKA-regulated mRNA destabilization pathway.