Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo.
Angiotensin type 2 (AT(2)) receptors for angiotensin II suppress cell growth and induce apoptosis in vitro, but their role is poorly defined in vivo. We reported that transient induction of smooth muscle cell (SMC) apoptosis precedes DNA synthesis inhibition and aortic hypertrophy regression in spontaneously hypertensive rats treated with the AT(1) antagonist losartan or the converting-enzyme inhibitor enalapril. Although both drugs are equipotent in reducing SMC number, apoptosis occurs significantly earlier with losartan than enalapril. To examine the role of AT(2) receptors in this model, spontaneously hypertensive rats were given valsartan, an AT(1) antagonist, or enalapril, in combination or not with the AT(2) antagonist PD123319 for 1 or 2 weeks. Control rats received vehicle. Systolic blood pressure was reduced similarly by valsartan and enalapril but it was not significantly affected by PD123319. Angiotensin II plasma levels were increased (6-fold) with valsartan and reduced (80%) with enalapril but unaffected by PD123319. Valsartan significantly increased internucleosomal DNA fragmentation indicative of apoptosis at 1 week only (2.7-fold) and significantly reduced aortic mass (18%), SMC number (33%), and DNA synthesis (24%, measured by (3)H-thymidine incorporation) at 2 weeks. These valsartan-induced changes were prevented by PD123319. In contrast, enalapril-induced DNA fragmentation (2-fold increase at 2 weeks) was not affected by PD123319. PD123319 given alone did not affect growth or apoptosis. AT(1) and AT(2) receptor mRNAs were detected in the aorta by reverse transcription-polymerase chain reaction. Together, these results provide the first evidence that AT(2) receptors mediate vascular mass regression by stimulating SMC apoptosis in vivo, an effect seen during AT(1) receptor blockade but not during converting-enzyme inhibition.
Tea
B S
BS
Centre de Recherche, Centre Hospitaliér de l'Université de Montréal (CHUM), Montreal, Quebec, Canada.
Der Sarkissian
S
S
Touyz
R M
RM
Hamet
P
P
deBlois
D
D
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D009131:Muscle, Smooth, Vascular / Q000473:pathology* / Q000503:physiopathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000502:physiology*
D000959:Antihypertensive Agents; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D004656:Enalapril; D019808:Losartan