Manipulating angiotensin metabolism with angiotensin converting enzyme 2 (ACE2) in heart failure

Abstract

Angiotensin converting enzyme 2 (ACE2), is a monocarboxypeptidase which metabolizes several peptides including the degradation of Ang II, a peptide with vasoconstrictive/proliferative/effects, to generate Ang 1-7, which acting through its receptor Mas exerts vasodilatory/anti-proliferative actions. The classical pathway of the RAS involving the ACE-Ang II-AT₁ receptor axis is antagonized by the second arm constituted by the ACE2-Ang 1-7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure-overload and myocardial infarction. Human recombinant ACE2 is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis and diastolic dysfunction and suppresses pressure-overload induced heart failure. Due to its characteristics, the ACE2-Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of heart failure. Human recombinant ACE2 has been safely administered to healthy human volunteers intravenously resulting in sustained lowering of plasma Ang II levels. In this review, we will summarize the beneficial effects of ACE2 in heart disease and the potential use of human recombinant ACE2 as a novel therapy for heart failure.

Figure 1

Diverse signaling pathways and cellular effects induced ACE/Ang II/AT₁R and opposing effects of ACE2/Ang (1–7)/MasR. ACE mediated generation of Ang II results in activation of various signaling pathways resulting in adverse cardiac remodeling and cardiac dysfunction. Activation of ACE2/Ang (1–7)/MasR axis counter-regulates Ang II/AT1R mediated effects and also stimulates PI3K-Akt-eNOS pathway mediated cardiac contractility. ACE: angiotensin converting enzyme; Ang 1–7: angiotensin (1–7); Ang II: angiotensin II; AT₁R: ang II type 1 receptor; ARB: AT₁ receptor blocker; DAG: diacyl glycerol; eNOS: endothelial nitric oxide synthase; ERK1/2: extracellular signal-regulated kinases 1/2; IP3: inositol triphosphate; MasR: Mas receptor; Nox2: NADPH oxidase 2; p38-MAPK: p38-mitrogen activated protein kinase; PKC: protein kinase C; PI3K: Phosphatidylinositide 3-kinase; PLC: phospholipase C.

Figure 2

Summary of the effect of ACE2 on cardiac and renal systems. ACE2 is a type-1 transmembrane enzyme which converts Ang I into Ang (1–9) and Ang II into Ang (1–7). ACE2 possesses anti-hypertrophic, anti-fibrotic, anti-inflammatory effects on the cardiac system attributed to decreased ROS production, decreased MMP activity and deceased fibroblast remodeling. ACE2 demonstrates anti-fibrotic, anti-apoptotic and anti-inflammatory effects along with decreased ROS production and decreased mesangial matrix expansion. MMP: matrix metalloproteinase; ROS: reactive oxygen species.

Figure 3

The principle of ACE2 activity assays. (a) ACE2, a membrane-bound carboxypeptidase, metabolizes quenched fluorescent substrate (QFS), to produce a fluorescent moiety which is then detected. Activity of the tissue sample is then determined using the difference in fluorescence between inhibited and uninhibited samples. (b) TACE/ADAM17, another membrane-bound protease, cleaves off the enzymatically active N-terminal domain of ACE2. Circulating ACE2 can be detected in plasma samples using a similar fluorescence protocol. TACE/ADAM17-mediated cleavage of ACE2 is also a mechanism by which RAS dysregulation is thought to occur in cardiac pathologies.