ACE2 Receptor System & Peptide Signaling

Angiotensin-converting enzyme 2 (ACE2) became globally recognized in 2020 as the entry receptor for SARS-CoV-2. But its primary biological function — operating as a critical counter-regulatory arm of the renin-angiotensin system (RAS) — is far more consequential for human physiology and represents a significant therapeutic target for peptide-based interventions.

The classical RAS axis

Understanding ACE2 requires context from the classical RAS pathway. When blood pressure drops or sodium levels fall, the kidneys release renin, which cleaves angiotensinogen (produced by the liver) into angiotensin I (Ang I), an inactive decapeptide. Angiotensin-converting enzyme (ACE), located primarily on pulmonary endothelial cells, removes two C-terminal amino acids from Ang I to produce angiotensin II (Ang II), the primary effector peptide.

Ang II signals through AT1 receptors to produce vasoconstriction, aldosterone secretion, sodium retention, sympathetic activation, and pro-inflammatory and pro-fibrotic effects. This axis is essential for acute blood pressure maintenance but, when chronically overactivated, drives hypertension, cardiac hypertrophy, renal fibrosis, and vascular inflammation. ACE inhibitors and AT1 receptor blockers (ARBs) — two of the most widely prescribed drug classes globally — work by suppressing this arm.

ACE2 and the counter-regulatory axis

ACE2 acts as a physiological brake on the classical RAS. It is a zinc metalloprotease that cleaves a single amino acid from the C-terminus of Ang II, converting the octapeptide Ang II (1-8) into the heptapeptide angiotensin 1-7 (Ang 1-7). This single amino acid removal fundamentally changes the peptide's biological activity.

Ang 1-7 signals primarily through the Mas receptor (MasR), a G-protein-coupled receptor that produces effects essentially opposite to Ang II/AT1 signaling:

• Vasodilation — Mas receptor activation stimulates endothelial nitric oxide synthase (eNOS), increasing nitric oxide production and relaxing vascular smooth muscle
• Anti-inflammatory — suppresses NF-kB signaling, reduces pro-inflammatory cytokine production (TNF-alpha, IL-6), and inhibits leukocyte adhesion to endothelium
• Anti-fibrotic — reduces TGF-beta signaling and collagen deposition in heart, kidney, and lung tissue
• Anti-thrombotic — inhibits platelet aggregation via nitric oxide and prostacyclin release
• Anti-hypertrophic — opposes Ang II-driven cardiac myocyte enlargement

ACE2 also cleaves other peptide substrates, including des-Arg9-bradykinin, apelin-13, and dynorphin A, though the Ang II to Ang 1-7 conversion is considered its most physiologically important function.

Tissue distribution and regulation

ACE2 is a type I transmembrane protein expressed on the surface of cells in the heart (cardiomyocytes, coronary endothelium), kidneys (proximal tubular epithelium), lungs (type II alveolar epithelial cells), intestine (enterocytes), brain (neurons, glial cells), and vascular endothelium throughout the body.

Expression is regulated by several factors. ACE inhibitors and ARBs upregulate ACE2 expression — a pharmacologically beneficial effect, as increased ACE2 shifts the RAS balance toward the protective Ang 1-7/Mas axis. Conversely, high Ang II levels, oxidative stress, and inflammatory cytokines can promote ACE2 shedding from the cell surface via ADAM17 (a disintegrin and metalloproteinase 17), releasing a soluble form (sACE2) into the circulation and reducing membrane-bound enzymatic activity.

ACE2 as SARS-CoV-2 entry receptor

The SARS-CoV-2 spike protein binds ACE2 with high affinity via its receptor-binding domain (RBD). This binding initiates viral entry through membrane fusion (facilitated by TMPRSS2 protease cleavage of the spike protein) or endocytosis. Upon viral binding, ACE2 is internalized and downregulated, reducing its enzymatic activity on the cell surface.

This ACE2 downregulation has direct pathological consequences: reduced conversion of Ang II to Ang 1-7 leads to unopposed Ang II/AT1 signaling — vasoconstriction, inflammation, fibrosis, and thrombosis. This RAS imbalance contributes to the acute respiratory distress syndrome (ARDS), myocarditis, and coagulopathy observed in severe COVID-19. The lung injury is not purely viral — it is partly a consequence of losing the ACE2 counter-regulatory brake.

Peptide-based therapeutic strategies

The ACE2/Ang 1-7/Mas axis presents multiple peptide-based therapeutic opportunities:

Recombinant soluble ACE2 (rhACE2). Administered as an infusion, soluble ACE2 serves a dual purpose: it acts as a decoy receptor that binds SARS-CoV-2 spike protein (preventing cell entry) while simultaneously converting circulating Ang II to Ang 1-7 (restoring RAS balance). Clinical trials with human recombinant soluble ACE2 (APN01) in COVID-19 patients have shown reductions in Ang II levels and viral load, though large-scale efficacy data remains limited.

Ang 1-7 analogs. Direct administration of Ang 1-7 or stabilized analogs activates the Mas receptor without depending on ACE2 enzymatic activity. The native heptapeptide has a short half-life (approximately 10-15 seconds in plasma due to rapid degradation by ACE, neprilysin, and aminopeptidases), necessitating continuous infusion or structural modification. Cyclized Ang 1-7 analogs and those incorporating D-amino acid substitutions at susceptible cleavage sites show extended half-lives in preclinical models.

Mas receptor agonists. Synthetic peptide and non-peptide agonists targeting the Mas receptor bypass the ACE2 pathway entirely. AVE 0991, a non-peptide Mas agonist, has shown cardioprotective and renoprotective effects in animal models, though clinical translation remains early.

DIZE (diminazene aceturate). This small molecule activates ACE2 enzymatic activity and has shown protective effects in animal models of pulmonary hypertension, myocardial infarction, and cerebral ischemia. It is not a peptide itself but enhances endogenous peptide processing through the ACE2 axis.

Clinical relevance beyond COVID-19

The ACE2/Ang 1-7/Mas pathway has therapeutic relevance far beyond viral disease. Preclinical data supports potential applications in heart failure (where Ang 1-7 improves cardiac output and reduces fibrosis), diabetic nephropathy (renoprotective effects independent of blood pressure reduction), pulmonary fibrosis, and hepatic fibrosis. The challenge remains delivering Ang 1-7 or its analogs with sufficient half-life and tissue penetration to achieve consistent pharmacological effects in humans.