Angiotensin-converting enzyme 2 in the brain: properties and future directions

Abstract

Angiotensin (Ang)-converting enzyme (ACE) 2 cleaves Ang-II into the vasodilator peptide Ang-(1-7), thus acting as a pivotal element in balancing the local effects of these peptides. ACE2 has been identified in various tissues and is supposed to be a modulator of cardiovascular function. Decreases in ACE2 expression and activity have been reported in models of hypertension, heart failure, atherosclerosis, diabetic nephropathy and others. In addition, the expression level and/or activity are affected by other renin-angiotensin system components (e.g., ACE and AT1 receptors). Local inhibition or global deletion of brain ACE2 induces a reduction in baroreflex sensitivity. Moreover, ACE2-null mice have been shown to exhibit either blood pressure or cardiac dysfunction phenotypes. On the other hand, over-expression of ACE2 exerts protective effects in local tissues, including the brain. In this review, we will first summarize the major findings linking ACE2 to cardiovascular function in the periphery then focus on recent discoveries related to ACE2 in the CNS. Finally, we will unveil new tools designed to address the importance of central ACE2 in various diseases, and discuss the potential for this carboxypeptidase as a new target in the treatment of hypertension and other cardiovascular diseases.

Figure 1

Working model for the brain renin‐angiotensin system. Angiotensinogen produced by glial cells is transformed by renin to form Ang‐I, which is then converted by ACE into Ang‐II. This octapeptide can be hydrolyzed by ACE2 to form Ang‐(1–7) or converted to the heptapepetide Ang‐III by aminopeptidase A (APA) and further degraded to Ang‐IV by aminopeptidase N (APN). ACE2 also cleaves Ang‐I to Ang‐(1–9), the latter being converted by ACE into Ang‐(1–7). Ang‐(1–7) can also be formed by neprilysin (NEP) from Ang‐I or Ang‐(1–9). ACE metabolizes Ang‐(1–7) to the inactive peptide Ang‐(1‐5). The recently discovered Ang‐(1‐12) could originate from AGT and potentially generate Ang‐II or Ang‐(1–7). Ang‐II acting on AT1 receptors (AT1R) can activate mitogen‐activated protein kinase kinase (MAPKK), leading to enhanced p38 kinase activity, phosphorylation of ERK1/2 and increased expression of c‐jun and c‐fos. AT1R also ultimately increase reactive oxygen species (ROS) production via NAD(P)H oxidase (not represented here). On the other side AT2R oppose AT1R‐mediated signaling. Ang‐(1–7) acting on the Mas receptor may attenuate the actions of the ACE/Ang‐II/AT1R pathway through inhibition of the MAPKK pathway and stimulation of nitric oxide (NO) release. In addition to Ang‐II, renin binding to (Pro)renin receptors (PRR) and Ang‐III binding to AT1R also trigger activation of the MAPKK–ERK1/2 signaling pathway. AT4R/IRAP activation induces c‐fos expression and probable NO release.

Figure 2

Engineering of brain‐selective ACE2 transgenic mouse models. (a) Syn‐hACE2 mice. The full open reading frame of the human ACE2 gene (hACE2) is driven by a synapsin promoter, and the syn‐hACE2 construct was injected into a 1‐cell mouse embryo. Transgenic syn‐hACE2 mice express hACE2 protein specifically in neurons. (b) ‘Brain‐only ACE2’ mice (bACE2). By breeding ACE2^−/y (white) with the syn‐hACE2 line (green), we generated a transgenic mouse model over‐expressing ACE2 in the brain while lacking the enzyme in the periphery (black). (c) SARA mice. The breeding strategy first consisted in generating double transgenic mice expressing both syn‐hACE2 (green) and R⁺ (human renin gene), or A⁺ (human AGT gene) constructs. These mice were then bred together to generate the triple transgenic SARA mice (yellow) in which brain‐selective over‐expression of ACE2 is in a position to counter the hyperactive RAS.