Expression of cell cycle proteins in blood vessels of angiotensin II-infused rats - Role of AT(1) receptors

Angiotensin II is an important modulator of cell growth through AT(1) recep tors, as demonstrated both in vivo and in vitro. We investigated the role o f proteins involved in the cell cycle, including cyclin D1, cyclin-dependen t kinase 4 (cdk4), and cyclin-dependent kinase inhibitors p21 and p27 in bl ood vessels of angiotensin II-infused rats and the effect therein of the AT (1)-receptor antagonist losartan. Male Sprague-Dawley rats were infused for 7 days with angiotensin II (120 ng/kg per minute SC) and/or treated with l osartan (10 mg/kg per day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled H-3-thymidine incorporation. The expression of c yclin D1, cdk4, p21, and p27, which play critical roles during the G(1)-pha se of the cell cycle process, was examined by Western blot analysis. Tail-c uff systolic blood pressure (mm Hg) was elevated (P<0.01, n=9) in angiotens in II-infused rats (161.3+/-8.2) versus control rats (110.1+/-5.3) and norm alized by losartan (104.4+/-3.2). Radiolabeled H-3-thymidine incorporation (cpm/100 <mu>g DNA) showed that angiotensin II infusion significantly incre ased DNA synthesis (152+/-5% versus 102+/-6% of control rats, P<0.05). Expr ession of cyclin D1 and cdk4, was significantly increased in the angiotensi n II group to 213.7+/-8% and 263.6+/-37% of control animals, respectively, whereas expression of p21 and p27 was significantly decreased in the angiot ensin Ii group to 23.2+/-10.4% and 10.3+/-5.3% of control animals, respecti vely. These effects induced by angiotensin II were normalized in the presen ce of losartan. Thus, when AT(1) receptors are stimulated in vivo, DNA synt hesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Red uction in cell cycle kinase inhibitors p21 and p27 may contribute to activa tion of growth induced by in vivo AT(1) receptor stimulation.