The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice

Abstract

During several months of 2002, severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (SARS-CoV) spread rapidly from China throughout the world, causing more than 800 deaths due to the development of acute respiratory distress syndrome (ARDS), which is the severe form of acute lung injury (ALI). Interestingly, a novel homologue of angiotensin-converting enzyme, termed angiotensin-converting enzyme 2 (ACE2), has been identified as a receptor for SARS-CoV. Angiotensin-converting enzyme and ACE2 share homology in their catalytic domain and provide different key functions in the renin-angiotensin system (RAS). Angiotensin-converting enzyme cleaves angiotensin I to generate angiotensin II, which is a key effector peptide of the system and exerts multiple biological functions, whereas ACE2 reduces angiotensin II levels. Importantly, our recent studies using ACE2 knockout mice have demonstrated that ACE2 protects murine lungs from ARDS. Furthermore, SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo, which can be attenuated by blocking the renin-angiotensin pathway, suggesting that the activation of the pulmonary RAS influences the pathogenesis of ALI/ARDS and SARS.

Figure 1

Current view of ACE and ACE2 functions 
Angiotensin I serves as a substrate for both ACE and ACE2. Angiotensin II is known to act as a vasoconstrictor in vivo. The function of angiotensin(1–9) is not well understood. Both ACE and ACE2 are involved in the production of the vasodilator peptide angiotensin(1–7).

Figure 2

Schematic diagram of the proposed role of the renin–angiotensin system in development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) 
Upon insults such as acid aspiration and sepsis, the generation of Ang II from Ang I is mediated by ACE. Angiotensin II contributes to acute lung failure through stimulation of the AT₁R, while ACE2 and AT₂R negatively regulate this pathway and protect from acute lung failure. However, additional ACE2‐regulated but Ang II‐independent pathways seem to contribute to ALI/ARDS.

Figure 3

Schematic diagram of the role of the renin–angiotensin system in acute lung failure and proposed SARS‐CoV action 
In acute lung injury, such as acid aspiration, pneumonia or sepsis, the generation of Ang II from Ang I is enhanced by ACE, and Ang II induces acute lung failure through stimulation of the AT₁R, while ACE2 and AT₂R negatively regulate this pathway and protect from acute lung failure. In contrast, SARS‐CoV infection is mediated through binding of the SARS Spike protein to ACE2 or liver/lymph node‐specific intercellular adhesion molecule‐3‐grabbing nonintegrin (L‐SIGN) and downregulates the protective molecule ACE2, thus leading to severe lung injury and acute lung failure.