Angiotensin-Converting Enzyme 2, known as ACE2, is a protein found on the surface of many cells throughout the human body. It functions as an enzyme, playing a role in various physiological processes. Its broad distribution and diverse biological roles have made it a subject of significant scientific attention.
Understanding ACE2
ACE2 is a zinc metalloenzyme and carboxypeptidase. It can be found either attached to the cell membrane (mACE2) or in a soluble form (sACE2). Its main role is within the Renin-Angiotensin System (RAS), a complex network regulating blood pressure, fluid, and electrolyte balance. High expression of ACE2 is found in the intestines, kidney, testis, gallbladder, heart, and lung, particularly in type II alveolar epithelial cells.
The classical RAS pathway involves angiotensin-converting enzyme (ACE), which converts angiotensin I into angiotensin II, a potent vasoconstrictor that raises blood pressure. ACE2 acts as a counterbalance to ACE by degrading angiotensin II into angiotensin (1-7). Angiotensin (1-7) then binds to MasR receptors, leading to localized vasodilation, a decrease in blood pressure, and promoting anti-inflammatory and anti-fibrotic actions.
ACE2’s catalytic efficiency for angiotensin II is significantly higher than for angiotensin I, approximately 400-fold greater, indicating its primary role in breaking down the vasoconstrictive angiotensin II. This action helps to mitigate the effects of angiotensin II, making it a promising drug target for cardiovascular diseases.
ACE2 and Viral Interactions
ACE2 serves as a cellular entry receptor for certain viruses, including SARS-CoV-2, the virus responsible for COVID-19. The spike (S) glycoprotein on the surface of SARS-CoV-2 is the key viral component that binds to ACE2. The S protein consists of S1 and S2 subunits, with the S1 subunit containing the receptor-binding domain (RBD).
The binding occurs when the RBD of the S1 subunit specifically attaches to the large membrane-distal face of human ACE2. This interaction is often described as a “lock-and-key” mechanism. The affinity of SARS-CoV-2’s spike protein for ACE2 is notably high, estimated to be around 15 nanomolar (nM), which is up to 20-fold greater than that of SARS-CoV, potentially contributing to COVID-19’s higher transmissibility.
After binding, the pre-fusion spike protein undergoes conformational changes, and host proteases cleave the spike protein. This cleavage event is necessary for the fusion of the viral membrane with the host cell membrane, allowing the viral genetic material to enter the cell. Upon viral entry, the surface ACE2 receptors may be internalized, leading to a reduction in available ACE2 on the cell surface. This downregulation of ACE2 activity can result in an accumulation of angiotensin II, potentially contributing to an imbalance in the renin-angiotensin system and influencing disease progression and lung injury.
ACE2’s Wider Biological Roles
Beyond its role in viral entry, ACE2 performs several important physiological functions across multiple organ systems. It is broadly distributed in tissues such as the heart, kidneys, lungs, liver, small intestine, and brain, though its expression levels can vary.
In the lungs, ACE2 helps regulate circulating angiotensin II levels, protecting against acute lung injury. It prevents vasoconstriction and fibrotic processes in lung epithelial cells, while simultaneously producing angiotensin (1-7), which has protective effects against pulmonary hypertension and vascular damage.
In the heart, ACE2 is an important regulator of cardiac function. It contributes to mitigating cardiac remodeling and supporting the cardioprotective effects of certain cardiovascular medications, suggesting its role in maintaining a healthy heart.
Within the kidneys, ACE2 is highly expressed. It contributes to blood pressure control and is involved in regulating amino acid absorption and transport in the kidney. Downregulation of ACE2 protein levels in the kidneys has been linked to conditions like hypertension and diabetic nephropathy, suggesting its protective role in renal function. Furthermore, ACE2 is present in the gastrointestinal tract, maintaining gut health.
Factors Influencing ACE2 Expression
The expression and activity of ACE2 can be influenced by a variety of intrinsic and extrinsic factors. Biological elements such as age and sex play a role, with studies indicating higher ACE2 expression in older individuals and females.
Genetic factors also contribute, as variations in the ACE2 gene can be associated with differences in blood pressure and cardiovascular risks, particularly in individuals with type 2 diabetes mellitus. Underlying medical conditions, including hypertension and cardiocerebrovascular diseases, have been observed to correlate with higher ACE2 expression.
Certain medications can impact ACE2 expression. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs), commonly used to treat hypertension, have been shown to maintain or even enhance ACE2 expression levels. Lifestyle factors, such as smoking, hypoxia, and obesity, are also factors that can influence ACE2 expression.
Research and Therapeutic Potential
Ongoing research explores the therapeutic potential of modulating ACE2 activity for various medical conditions. One promising strategy involves using recombinant human soluble ACE2 as a decoy receptor. This soluble form can bind to viruses like SARS-CoV-2, preventing them from attaching to membrane-bound ACE2 on host cells and thus blocking viral entry.
Beyond viral infections, ACE2 is a target for treating cardiovascular diseases and lung injuries. Drugs that activate ACE2, including some ACE inhibitors, are being investigated for their potential to restore ACE2’s protective effects, especially when its expression is downregulated during disease states. These research avenues aim to leverage ACE2’s multifaceted roles for developing novel therapeutic interventions.