Food-Derived Up-Regulators and Activators of Angiotensin Converting Enzyme 2: A Review

Figures

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  Figure 1. Multifunctional roles of ACE2: SARS-CoVs entry, the RAS regulation, and amino acid transport. (A) ACE2 is the entry receptor of SARS-CoV-2, via interaction with the spike protein of the virus. (B) Ang II increases blood pressure via binding with the Ang II type 1 receptor (AT1R). ACE2 catalyzes the degradation of a vasoconstrictor Ang II to generate vasodilator Ang (1–7). The subsequent binding of Ang (1–7) to Mas receptor (MasR) contributes to the reduction of blood pressure. (C) ACE2 collaborates with the broad neutral amino acid transporter 1 (B0AT1) to facilitate the transport of neutral amino acids in the gut (created with BioRender).

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  Figure 2. Two heterodimers of ACE2 and B0AT1 combine to form dimers through the neck region of ACE2. ACE2 is composed of an N-terminal protease domain and a C-terminal collectrin-like domain. In its protease domain, the binding sites for spike protein interaction, substrate catalysis, and modulation of enzymatic activity are distinctly segregated. Two widely recognized ACE2 activators, diminazene aceturate (DIZE), and xanthenone (XTN), specifically target the hinge-bending domain, thereby increasing the activity of ACE2. The C-terminal domain contains a neck domain, an intracellular tail, and a transmembrane helix, serving as an anchor that enables ACE2 to localize on the cell membrane. The soluble form of ACE2 is produced through the cleavage of a disintegrin and metalloproteinase 17 (ADAM17) between the neck domain and the transmembrane helix (created with BioRender).

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  Figure 3. The multifaceted impact of ACE2 on various diseases. Decreased ACE2 activity contributes to heightened Ang II production, amplifying inflammation, and triggering excessive oxidative stress. This cascade culminates in dysfunction across vascular, cardiac, pulmonary, hepatic, and renal systems. Meanwhile, Ang II influences adipose tissue and liver, disrupting the normal metabolism of glucose and lipids (created with BioRender).

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  Figure 4. Proposed mechanisms of ACE2 regulation. (A) SARS-CoV-2 enters cells by binding to the ACE2 receptor. The virus-mediated ACE2 translocation downregulates ACE2 levels on the cellular membrane. (B) Accumulation of Ang II, resulting from the loss of ACE2, activates ADAM17. This activation, in turn, mediates the proteolytic cleavage of ACE2, leading to the production of soluble ACE2 (sACE2) in the circulation. (C) ACE2 inactivates apelin by removing phenylalanine residue, while simultaneously, apelin can promote ACE2 expression. (D) Epigenetic changes, such as histone methylation and acetylation, affect ACE2 gene expression, while (E) miRNAs negatively regulate ACE2 gene expression by cleaving ACE2 mRNA or inhibiting its translation. (F) Various transcription factors participate in ACE2 transcription. Certain transcription factors, like FXR and Nrf2, bind to their respective responsive elements in the ACE2 promoter region, regulating ACE2 expression. Others directly interact with the ACE2 promoter region upon stimulation by upstream molecules (created with BioRender).

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  Figure 5. Natural and synthetic sources of ACE2 activators and up-regulators. Effective doses and treatment durations of each compound used in in vivo studies are included. All compounds are administered orally, except where specified otherwise (created with BioRender).

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  Figure 6. Bioactive peptides with ACE2 activating/up-regulatory activities (created with BioRender).