Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors.
We investigated in Lewis normotensive rats the effect of coronary artery ligation on the expression of cardiac angiotensin-converting enzymes (ACE and ACE 2) and angiotensin II type-1 receptors (AT1a-R) 28 days after myocardial infarction. Losartan, olmesartan, or the vehicle (isotonic saline) was administered via osmotic minipumps for 28 days after coronary artery ligation or sham operation. Coronary artery ligation caused left ventricular dysfunction and cardiac hypertrophy. These changes were associated with increased plasma concentrations of angiotensin I, angiotensin II, angiotensin-(1-7), and serum aldosterone, and reduced AT1a-R mRNA. Cardiac ACE and ACE 2 mRNAs did not change. Both angiotensin II antagonists attenuated cardiac hypertrophy; olmesartan improved ventricular contractility. Blockade of the AT1a-R was accompanied by a further increase in plasma concentrations of the angiotensins and reduced serum aldosterone levels. Both losartan and olmesartan completely reversed the reduction in cardiac AT1a-R mRNA observed after coronary artery ligation while augmenting ACE 2 mRNA by approximately 3-fold. Coadministration of PD123319 did not abate the increase in ACE 2 mRNA induced by losartan. ACE 2 mRNA correlated significantly with angiotensin II, angiotensin-(1-7), and angiotensin I levels. These results provide evidence for an effect of angiotensin II blockade on cardiac ACE 2 mRNA that may be due to direct blockade of AT1a receptors or a modulatory effect of increased angiotensin-(1-7).
Hypertension and Vascular Disease Center, Wake Forest University Health Science Center, Winston-Salem, NC 27157, USA.
Yuichiro
Y
Ishiyama
Patricia E
PE
Gallagher
David B
DB
Averill
E Ann
EA
Tallant
K Bridget
KB
Brosnihan
Carlos M
CM
Ferrario
D000803:Angiotensin I / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D000804:Angiotensin II / Q000097:blood / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002268:Carboxypeptidases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000517:prevention & control*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008026:Ligation; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D000068557:Olmesartan Medoxomil; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; 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); D019808:Losartan