Regulation of AT1 Angiotensin
Receptor Gene Expression in Vascular Smooth Muscle Cells
Contact Person: TJ Murphy (email@example.com)
Several classes of agonists down regulate AT1-receptor gene expression in rat vascular smooth muscle cells (VSMC). This is associated with a fairly rapid loss of the AT1-R mRNA. New studies in VSMC provide direct evidence that regulation of AT1-R mRNA levels is a dominant pathway for specification of cell surface AT1-R protein levels. Agonists of growth factor and Gq-coupled receptors inhibit transcription of the AT1-R gene, but little is understood about how this occurs mechanistically. However, this effect alone cannot fully explain the loss of mRNA stimulated by agonists. Cyclic AMP-elevating agents do not affect VSMC AT1-R gene transcription, and protein kinase A mediated destabilization of the AT1-R mRNA contributes substantially to AT1-R down regulation by some, but not all classes of agonists. Powerful new systems, including a retroviral tetracycline regulated vector, have been created to express recombinant AT1-R minigenes in VSMC. With these, post-transcriptional processes can be experimentally separated from the complications of transcriptional effects by agonists on the native gene. Their use is accelerating our understanding of the mechanisms underlying signaling-regulated AT1-R mRNA stability control in VSMC.
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