In recent times, the angiotensin-converting enzyme 2 (ACE2) protein has garnered significant attention due to its identification as a key receptor for the SARS-CoV-2 virus. However, investigations into ACE2 have unearthed its potential as a therapeutic target for various diseases, sparking keen research interest.
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What is ACE2
ACE2 is a cell membrane protein with its enzymatic domain located on the outer surface of human cells. Initially identified as a homologous or variant protein of angiotensin-converting enzyme (ACE), ACE2 operates in contrast to ACE under normal physiological conditions. ACE, a well-explored enzyme, promotes the conversion of angiotensin I (Ang I) to angiotensin II (Ang II), functioning as a vasoconstrictor that contributes to the constriction of blood vessel walls and the narrowing of vessel lumens.
In contrast, ACE2 plays a crucial role in vasodilation, opposing the actions of ACE. Its primary function involves the relaxation of blood vessel walls. Both ACE and ACE2 are integral components of the renin-angiotensin system (RAS), a pivotal regulatory system that governs blood pressure and various organs such as the lungs, heart, and kidneys. The RAS serves as a vital system for maintaining proper blood supply throughout the body under normal physiological conditions.
Function of ACE2
The renin-angiotensin system encompasses a range of regulatory enzymes, peptide hormones, and their corresponding receptors. Angiotensinogen, originating from the liver, serves as the precursor of angiotensin (Ang). Renin, an enzyme in the kidneys, cleaves angiotensinogen to generate Ang I, which is subsequently converted to Ang II through the action of ACE. Ang II, an eight-amino-acid hormone peptide, binds to type 1 angiotensin receptors (AT1R) on the surface of smooth muscle cells in small blood vessels, leading to vasoconstriction. Additionally, Ang II stimulates the reabsorption of sodium by the kidneys. The combined effects of vasoconstriction and increased sodium reabsorption contribute to elevated blood pressure. Consequently, heightened ACE activity can result in elevated Ang II levels, ultimately leading to hypertension.
Conversely, ACE2 facilitates the conversion of Ang II into a peptide comprising seven amino acids, namely Ang 1-7. The actions of Ang 1-7 stand in stark contrast to those of Ang II. Upon activation by Ang 1-7, its receptor protein, Mas receptor (MasR), promotes vasodilation, leading to a reduction in blood pressure. Furthermore, ACE2 cleaves Ang I into Ang 1-9, effectively counteracting ACE by eliminating the substrate (Ang I). To sum up, ACE2 plays a pivotal role in balancing vasoconstriction and vasodilation while regulating blood pressure. This is achieved by promoting the conversion of Ang II to Ang (1-7) and Ang I to Ang 1-9. Through the transformation of Ang II into Ang (1-7) and Ang I into Ang 1-9, ACE2 actively contributes to maintaining the equilibrium between vasoconstriction and vasodilation, ensuring the preservation of normal blood pressure.
Fig. 1 The renin-angiotensin system (RAS) and ACE2/angiotensin-(1–7)/MAS axis (Ni W., et al. 2020).
The Role of ACE2 in SARS-CoV-2 Virus Infection
In the global pursuit of comprehending the intricacies of the SARS-CoV-2 virus and devising potential therapeutic interventions amid the onset of the COVID-19 pandemic, scholarly attention has been fervently directed toward ACE2-identified as the pivotal receptor for the virus. At the epicenter of this investigative endeavor lies the spike protein (S protein) adorning the virus's surface, establishing a crucial nexus with ACE2 and facilitating viral entry into human cells.
In addition, researchers have found that the process of virus entry into cells not only requires the docking of the S protein of SARS-CoV-2 and ACE2 on the cell surface but also requires the help of a variety of other proteins to promote the entry of the virus into cells. For example, proteases from the host cell are responsible for removing fragments from ACE2 and the S protein to enhance their affinity for binding to each other. Other proteins with enzymatic activity are responsible for modifying the ACE2-S protein complex and packaging it within the cell membrane to form vesicles to facilitate virus entry into host cells. Therefore, ACE2 and its interaction process with SARS-CoV-2, as well as various other enzymatically active proteins involved in this process, may become effective targets for anti-COVID-19 drugs.
ACE2 as a Target Protein for COVID-19 Treatment
Because ACE2 plays a crucial role in the invasion of host cells by SARS-CoV-2, researchers are currently working hard to develop drugs that can block its function as a viral receptor. To date, no small molecules have been approved for this disease through drug repurposing. However, a recently developed biologic drug candidate may be able to achieve this goal. This clinical-grade drug, human recombinant soluble ACE2 (hrsACE2), was originally designed for acute respiratory distress syndrome (ARDS).
As hrsACE2 lacks a membrane-penetrating structure, it remains unbound outside cells and does not adhere to human cells. Nevertheless, it possesses the capability to bind to the SARS-CoV-2 virus, functioning as a decoy receptor. Through competitive binding, it hinders the virus from attaching to native ACE2 on the cell surface, thereby impeding viral entry into host cells. Experimental studies using organoids and in vitro cultured cells have demonstrated that hrsACE2 effectively inhibits viral infection.
Moreover, a 2017 clinical trial revealed that patients with acute respiratory distress syndrome (ARDS) tolerated hrsACE2 well, leading to a rapid decrease in serum Ang II levels. With the potential to become the pioneering drug targeting ACE2, hrsACE2 holds promise for tailored therapies against COVID-19. Notably, combining hrsACE2 with remdesivir exhibits the potential to enhance treatment efficacy.
Beyond COVID-19, the ACE2 pathway offers a prospective avenue for addressing other respiratory diseases such as the 2009 novel influenza (H1N1) and avian influenza (H5N1). Recombinant ACE2 development, in collaboration with AT1R inhibitors or ACE inhibitors, may serve as a therapeutic approach. Additionally, the expanding focus on ACE2 in cardiovascular disease underscores its potential in targeting renin-angiotensin system hyperactivity, particularly in conditions like hypertension. ACE2 emerges as a significant target in treating type 2 diabetes, where leveraging ACE2-mediated pathways could counteract the effects of overactive Ang II in diabetic kidneys.
References
- Imai Y.; et al. Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circulation Journal. 2010, 74(3): 405-410.
- Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock. 2016, 46(3): 239-248.
- Ni W.; et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Critical Care. 2020, 24(1): 1-10.
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