Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats.
When increased in vascular tissues, angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase that hydrolyzes angiotensin II to angiotensin-(1-7), may augment the growth inhibitory and vasodilatory effects of the heptapeptide. We investigated the regulation of ACE2 and angiotensin-(1-7) expression in aortas and carotid arteries of 12-wk-old male spontaneously hypertensive rats (SHR) by determining the effect of sustained angiotensin type 1 (AT(1)) receptor blockade with olmesartan (10 mg.kg(-1).day(-1), n = 13) compared with those that received atenolol (30 mg.kg(-1).day(-1), n = 13), hydralazine (10 mg.kg(-1).day(-1), n = 13), or vehicle (n = 21). Systolic blood pressures were approximately 30% lower (P < 0.05) in rats treated for 2 wk with olmesartan compared with vehicle-treated rats. Both atenolol and hydralazine produced similar decreases in systolic blood pressure. ACE2 mRNA in the thoracic aorta of olmesartan-treated rats (n = 8) was fivefold greater (P < 0.05) than that in vehicle-treated rats (n = 16), whereas atenolol (n = 8) or hydralazine (n = 8) had no effect. Immunostaining intensities in rats treated with olmesartan (n = 5) were also associated with increased (P < 0.05) ACE2 and angiotensin-(1-7) in thoracic aorta media compared with vehicle-treated rats. In contrast, immunostaining intensities for both ACE2 and angiotensin-(1-7) were not different from vehicle (n = 5) in carotid arteries of SHR medicated with either atenolol (n = 5) or hydralazine (n = 5). A comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio (P < 0.05) and media thickness (P < 0.05) without an effect on carotid artery morphometry. Compared with vehicle-treated SHR, vascular hypertrophy determined from media and lumen measurements was not changed in SHR given either atenolol or hydralazine. These data represent the first report of ACE2 and angiotensin-(1-7) expression in the aorta and carotid arteries of SHR. Increased ACE2 and angiotensin-(1-7) in association with altered dimensions of the thoracic aorta but not carotid arteries in response to olmesartan treatment provides evidence that this pathway is regulated by AT(1) receptors and may be important in mediating the pressure-independent vascular remodeling effects of angiotensin peptides.
Igase
Michiya
M
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
Strawn
William B
WB
Gallagher
Patricia E
PE
Geary
Randolph L
RL
Ferrario
Carlos M
CM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000803:Angiotensin I / Q000097:blood / Q000235:genetics*; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology*; D001262:Atenolol / Q000494:pharmacology; D002268:Carboxypeptidases / Q000235:genetics* / Q000378:metabolism; D002339:Carotid Arteries / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D000068557:Olmesartan Medoxomil; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics*; D007703:Peptidyl-Dipeptidase A; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D010446:Peptide Fragments; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014665:Vasodilator Agents; D000804:Angiotensin II; D006830:Hydralazine; D001262:Atenolol; D000068557:Olmesartan Medoxomil; D000803:Angiotensin I; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)