The one-two punch: knocking out angiotensin II in the heart

Abstract

Ang II plays an important role in the pathophysiology of cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors lower Ang II levels by inhibiting conversion of Ang I to Ang II, but Ang II levels have been shown to return to normal with chronic ACE inhibitor treatment. In this issue of the JCI, Wei et al. show that ACE inhibition induces an increase in chymase activity in cardiac interstitial fluid, providing an alternate pathway for Ang II generation.

Figure 1. The renin-angiotensin system.

AGT is cleaved by either renin or cathepsin to form Ang I. Ang I is cleaved by ACE or chymase to form Ang II or by ACE2 to form Ang-(1–9). Ang II binds to one of the Ang II receptors to exert its downstream effects on cardiovascular function, with AT1 and AT2 working in opposition to each other. Ang-(1–12) is an alternative precursor for Ang I and II. Ang-(1–7) is formed through cleavage of Ang II by ACE2 or cleavage of Ang-(1–9) by ACE and binds to the Mas receptor. The ACE–Ang II–AT1 axis and the ACE2–Ang-(1–7)–Mas axis appear to have opposing functions. ACE also degrades BK, serving as a link between the RAS and the kallikrein/kinin system, while chymase is also important in tissue remodeling.

Figure 2. ACE inhibition induces chymase release, which prevents decreased Ang II formation.

ACEI enters the interstitium from the systemic circulation and inhibits degradation of BK by ACE. Increased BK signaling through the B2R leads to chymase release, creating an alternative pathway for Ang II generation and contributing to adverse cardiac tissue remodeling. Inhibition of B2R signaling by Hoe-140 prevents ACEI-induced chymase release and suppresses Ang II formation. Similarly, LV function is improved by inhibition of chymase in conjunction with ACEI.