Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease

Abstract

Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1-7 (Ang 1-7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1-7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.

Figure 1

Schematic representation of the renin-angiotensin system (RAS) and the key balancing role of ACE2. Abbreviations, ACE: angiotensin-converting enzyme; ACE2: angiotensin-converting enzyme 2; NEP: neprilysin; AT1: Ang II type 1 receptor; AT2: Ang II type 2 receptor; PEP: prolyl endopeptidase; CAGE: chymostatin-sensitive angiotensin II-generating enzyme.

Figure 2

Increased plaque area accumulation in the aorta of Apoe/Ace2 double KO mice when compared to control Apoe KO mice [5]. *vs control Apoe KO mice P < 0.05.

Figure 3

Increased LV mass in Ace2 KO mice versus C57bl6 mice (unpublished data). *vs control C57Bl6 mice, P < 0.05.

Figure 4

Reduced ACE2 expression (arrows) in renal cortical tubules of diabetic mice (b) when compared to control mice (a) [27].