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) receptors, as demonstrated both in vivo and in vitro. We investigated the role of proteins involved in the cell cycle, including cyclin D1, cyclin-dependent kinase 4 (cdk4), and cyclin-dependent kinase inhibitors p21 and p27 in blood 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 losartan (10 mg/kg per day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled (3)H-thymidine incorporation. The expression of cyclin D1, cdk4, p21, and p27, which play critical roles during the G(1)-phase of the cell cycle process, was examined by Western blot analysis. Tail-cuff systolic blood pressure (mm Hg) was elevated (P<0.01, n=9) in angiotensin II-infused rats (161.3+/-8.2) versus control rats (110.1+/-5.3) and normalized by losartan (104.4+/-3.2). Radiolabeled (3)H-thymidine incorporation (cpm/100 microgram DNA) showed that angiotensin II infusion significantly increased DNA synthesis (152+/-5% versus 102+/-6% of control rats, P<0.05). Expression of cyclin D1 and cdk4 was significantly increased in the angiotensin 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 angiotensin II group to 23.2+/-10.4% and 10.3+/-5.3% of control animals, respectively. These effects induced by angiotensin II were normalized in the presence of losartan. Thus, when AT(1) receptors are stimulated in vivo, DNA synthesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Reduction in cell cycle kinase inhibitors p21 and p27 may contribute to activation of growth induced by in vivo AT(1) receptor stimulation.
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
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El Mabrouk
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Schiffrin
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004247:DNA / Q000096:biosynthesis; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013152:Splanchnic Circulation
D057911:Angiotensin Receptor Antagonists; D018797:Cell Cycle Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D004247:DNA; D018844:Cyclin-Dependent Kinases; D019808:Losartan