Angiotensin-Converting Enzyme 2 (ACE2) is a protein found on the surface of many cells throughout the human body. This protein is a component of the body’s mechanisms for maintaining internal balance, particularly concerning blood pressure and inflammation. The ACE2 receptor has gained attention for serving as the primary entry point for coronaviruses, including the virus responsible for the COVID-19 pandemic. Understanding this protein requires looking at its function within the body’s complex regulatory systems and how certain viruses exploit it for infection.
What Are ACE2 Receptors and How Do They Function?
ACE2 is a cell-membrane-anchored enzyme, classified as a type I transmembrane protein, spanning the entire cell membrane with its active part facing outward. It has a single catalytic site, distinguishing it from its counterpart, ACE. This protein is a key player in the Renin-Angiotensin System (RAS), a hormonal cascade that regulates blood pressure, fluid balance, and inflammation.
The primary function of ACE2 is to act as a counter-regulator to the classical arm of the RAS, which is mediated by Angiotensin II (Ang II). Ang II is a powerful peptide that constricts blood vessels, increasing blood pressure and promoting inflammation and fibrosis. ACE2 exerts its balancing effect by cleaving Ang II, converting it into a smaller peptide called Angiotensin 1-7 (Ang 1-7).
Ang 1-7 is the natural counter-force to Ang II, acting as a vasodilator that widens blood vessels and lowers blood pressure. By generating Ang 1-7 and reducing Ang II, ACE2 helps protect the cardiovascular system and various organs from excessive inflammation and tissue damage. This enzymatic activity is fundamental to maintaining homeostasis.
Distribution Across Major Organ Systems
The physiological importance of ACE2 is reflected in its broad distribution across several major organ systems. The protein is expressed on cells in tissues interacting with the external environment or involved in fluid and pressure regulation, providing context for both its protective role and its vulnerability to viral attack.
In the respiratory system, ACE2 is abundant on Type II alveolar epithelial cells (pneumocytes). Its presence highlights its regulatory influence on lung function, including mitigating acute lung injury and inflammation. ACE2 is also found in the epithelial cells lining the upper bronchial and nasal passages.
Beyond the lungs, ACE2 expression is significant in the gastrointestinal tract, particularly on the brush border of enterocytes in the small intestine. Here, it regulates inflammation and nutrient absorption. The kidneys also express ACE2 on the proximal tubule cells, contributing to blood pressure and fluid reabsorption.
The cardiovascular system relies on ACE2, which is found on endothelial cells lining blood vessels and on cardiac muscle cells. In these tissues, breaking down Ang II prevents excessive vasoconstriction and fibrosis, supporting healthy heart function.
The Role of ACE2 in Viral Entry
The presence of the ACE2 receptor provides a specific pathway that certain viruses, notably SARS-CoV-2, exploit for cellular invasion. The process begins with the virus’s distinctive spike (S) protein, which covers the viral surface and acts as the binding mechanism.
The spike protein has a Receptor Binding Domain (RBD) shaped to fit precisely into the active site of the ACE2 enzyme, functioning like a key in a lock. This binding event is strong in SARS-CoV-2. Once the spike protein is attached, host cell proteases, such as TMPRSS2, prime the protein, facilitating the fusion of the viral and cellular membranes.
Following fusion, the virus injects its genetic material into the host cell, initiating replication. A significant consequence of this viral hijacking is the functional depletion, or downregulation, of available ACE2 receptors on the cell surface. The cell-surface ACE2 is either internalized along with the virus or shed from the membrane during entry.
This downregulation is detrimental because the loss of ACE2 protective function leads to an imbalance in the RAS. With fewer ACE2 enzymes available, the potent vasoconstrictor Ang II builds up in the local tissue environment. This hyperactivation of the Ang II pathway contributes directly to the inflammation and damage observed in the infected organs.
Implications for Disease and Therapeutic Targeting
The understanding of ACE2’s role in viral entry and its subsequent downregulation has profound implications for disease pathology and the development of targeted treatments. The accumulation of Ang II, resulting from the loss of ACE2’s enzymatic activity, drives inflammation and increases vascular permeability, which is damaging in the lungs. This imbalance can lead to acute lung injury and severe respiratory distress.
The systemic distribution of ACE2 explains why the disease can affect multiple organs beyond the respiratory tract, including the heart, kidneys, and blood vessels. Sustained elevation of Ang II, lacking its normal counterbalance, can exacerbate pre-existing cardiovascular conditions and contribute to the risk of clotting and organ failure. The core problem is the disruption of the body’s established homeostatic mechanism.
Researchers are investigating therapeutic strategies centered on the ACE2 axis to mitigate disease severity. One promising approach involves using human recombinant soluble ACE2 (hrsACE2), which acts as a molecular decoy. This manufactured protein circulates in the blood to bind the viral spike protein before the virus reaches membrane-bound ACE2 on cells.
This decoy strategy neutralizes the virus and allows natural ACE2 on cell surfaces to continue cleaving Ang II. Existing medications that modulate the RAS, such as ACE inhibitors and Angiotensin Receptor Blockers (ARBs), are also being studied for their indirect effects. These drugs do not directly interact with ACE2 but block the effects of Ang II or reduce its production, potentially counteracting the harmful consequences of ACE2 downregulation.