Upregulation of Angiotensin-Converting Enzyme 2 After Myocardial Infarction by Blockade of Angiotensin II Receptors

Abstract

Abstract-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 (AT 1a -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 AT 1a -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 AT 1a -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 AT 1a -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 AT 1a receptors or a modulatory effect of increased angiotensin-(1-7).

Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study

“…In addition, mice deficient in both ACE and ACE2 show completely normal heart function [25]. Thus ACE and ACE2 are thought to negatively regulate each other [26][27][28][29]. However, at this point, the full role of ACE2 in vivo and its impact on differences in response to ACE inhibitors and ARBs in women compared to men with CHF remain unknown.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…Indeed, chronic Ang-(1-7) treatment not only attenuated the development of heart failure in response to coronary artery ligation in rats (Loot et al 2002), but it also reversed cardiac hypertrophy and fibrosis in rats (Iwata et al 2005;Tallant et al 2005;Wang et al 2005;Grobe et al 2006a;2006b). Ishiyama et al (2004) found that heart failure induced by coronary artery ligation was associated with an increase in plasma Ang-(1-7) levels, which was augmented with the administration of the AT 1 receptor blockers losartan and olmesartan. The AT 1 -receptor blockade was associated with an upregulation of cardiac ACE2, suggesting that the increased Ang-(1-7) levels may be due to increased ACE2.…”

Comparison of the long-term effects of candesartan and olmesartan on plasma angiotensin II and left ventricular mass index in patients with hypertension

“…Whether the effects of several ARBs on ACE2 expression are same remains uncertain [10][11][12] especially in hypertensive patients. The present finding that the plasma Ang II level was decreased after replacement of candesartan with olmesartan without any changes in PRC suggests that the effect of olmesartan on ACE2 expression is more stimulating than that of candesartan.…”

“…[7][8][9] Takeda et al 10 reported that treatment with candesartan increased ACE2 mRNA level and decreased angiotensinogen mRNA level in the heart. Recently, it was shown that olmesartan increased ACE2 expression during the remodeling of the heart after myocardial infarction, 11 and olmesartan improved left ventricular remodeling with an increase in cardiac ACE2 expression in stroke-prone spontaneously hypertensive rats. 12 The ACE2 is a membrane-associated carboxy-peptidase that is highly expressed in the heart and kidney 13 and hydrolyzes Ang II to Ang 1-7, which inhibits the ACE C-domain and bradykinin by acting as an ACE inhibitor.…”