Previous studies have demonstrated that aging is associated with enhanced vascular smooth muscle cell (VSMC) proliferation which may, in part, explain observed morphological and functional vascular changes that occur with age. Angiotensin II is among the vasoactive agonists that have been implicated in VSMC proliferation. In preliminary studies, we isolated VSMC from the aortas of 6- and 24-month-old Fischer 344 rats in order to investigate age-associated changes in vascular angiotensin II receptors (AT receptors). Confluent, quiescent VSMC from aged rats showed a dramatic enhancement of AT receptor binding compared with young VSMC. At day 5 after plating cells, there was a two-fold increase in AT receptor binding in aged (1215+120 cpm/mg protein) compared with young VSMC (601 plus minus 90 cpm/mg protein). By day 7, the differential was striking: AT receptor binding in old VSMC was 1,588+90 cpm/mg protein versus receptor binding in young VSMC which had decreased by 4-fold to 204+18 cpm/mg protein. In contrast, the protein content on day 7 after being plating was 1.5-fold higher in young (6.0 plus minus +0.4 mg/dish) compared to old VSMC (3.9 plus minus 0.4 mg/dish). Pharmacological analysis revealed that alterations in AT receptor binding were due to changes in expression levels of the type-1 receptor (AT1); no differences in AT1 receptor affinities were observed between young and old VSMC. Cycloheximide (CHX) pretreatment abrogated the 50 percent decrease in AT1 receptor expression observed in young VSMC (control, 53 percent; CHX 134 percent). In contrast, CHX caused only a small insignificant reduction in AT1 receptor expression in old VSMC (control, 134 percent; CHX 126 percent). This grant application proposes to examine the age-related regulation of AT1 receptor gene expression in young and old VSMC. The three specific aims focusing on age-related changes of the AT1 receptor are: 1) Examine mRNA synthesis; 2) Assess mRNA stability; and 3) Study mRNA translation. Investigations into the molecular mechanisms governing the increased expression of AT1 receptors in aged VSMC could prove to be very interesting and instructive in light of known age-associated changes in the human vasculature, and open up a new area of research relative to human disease processes.
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