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(Hypertension. 1999;34:617-624.)
© 1999 American Heart Association, Inc.

Scientific Contributions

In Vivo Study of AT₁ and AT₂ Angiotensin Receptors in Apoptosis in Rat Blood Vessels

Quy N. Diep; Jin-Sheng Li; Ernesto L. Schiffrin

From the Medical Research Council of Canada Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.

Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}IRCM.qc.ca

Abstract—In vitro experiments suggest that angiotensin II (Ang II) may cause growth via angiotensin type 1 (AT₁) receptors and apoptosis via angiotensin type 2 (AT₂) receptors. To answer the question of whether AT₁ or AT₂ receptor activation could induce apoptosis in the vasculature in vivo, Wistar rats were infused for 7 days with Ang II (120 ng · kg^-1 · min^-1 subcutaneously) and treated with the AT₂ receptor antagonist PD 123319 (30 mg · kg^-1 · d^-1 subcutaneously) or the AT₁ receptor antagonist losartan (10 mg · kg^-1 · d^-1 orally). Apoptosis in thoracic aorta was quantified by radiolabeled DNA laddering and by terminal deoxynucleotide transferase–mediated dUTP nick end-labeling. The expression of p53, bax, bcl-2, and caspase-3, which play critical roles in apoptotic signaling, was examined by Western blot analysis. The mRNA expression of AT₁ and AT₂ receptors was determined by reverse transcription–polymerase chain reaction. The increase in systolic blood pressure and aortic growth induced by Ang II infusion was completely prevented by losartan alone or losartan given with PD 123319, whereas PD 123319 resulted in a greater increase in systolic blood pressure and aortic growth than Ang II alone. Radiolabeled DNA laddering showed that Ang II infusion±losartan or PD 123319 significantly increased apoptosis (147±8%, 178±20%, and 238±41%, respectively, P<0.05 compared with control). Expression of bax and active forms of caspase-3 was increased in the Ang II+PD 123319 group, whereas the expression of p53 and bcl-2 was not significantly different in all groups. The expression of AT₁ and AT₂ receptor mRNA was downregulated by losartan and PD 123319, respectively. Thus, when AT₁ or AT₂ receptors are stimulated in vivo, apoptosis is enhanced in the media of blood vessels. In the case of AT₁ receptor stimulation, this may occur secondary to vascular growth and modulate the latter. Both bax and caspase-3 participate in the pathways of apoptosis triggered by in vivo AT₁ receptor stimulation.

Key Words: muscle, smooth, vascular • apoptosis • angiotensin II • p53 • cysteine proteases

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