AOC3

Detailed Information

AOC3 (Amine Oxidase Copper Containing 3) encodes a copper-containing amine oxidase located on the cell surface and belongs to the semicarbazide-sensitive amine oxidase (SSAO) family. The gene is located on human chromosome 17q21.2, and its encoded product is commonly referred to as vascular adhesion protein-1 (VAP-1). Structurally, AOC3 is a homodimeric transmembrane protein, with each monomer comprising approximately 763 amino acids and a molecular weight of 85–90 kDa. Each monomer contains three key domains: an extracellular amine oxidase domain, a transmembrane anchor region, and a short intracellular tail. The extracellular domain contains two characteristic functional sites: a topaquinone (TPQ) cofactor at the active center and a copper-binding site (Cu²⁺), which together form the catalytic core of the enzyme.

The expression of AOC3 in the human body is highly tissue-specific. It is primarily expressed in vascular endothelial cells, especially high endothelial venules (HEVs), adipose tissue, smooth muscle cells, and certain epithelial cells. Under inflammatory conditions, the expression of AOC3 can be significantly upregulated by various pro-inflammatory cytokines such as TNF-α and IL-1β, promoting the translocation of AOC3 from intracellular storage vesicles to the cell surface. This pattern of regulation suggests a specific role for AOC3 in inflammatory responses.

Biological Functions and Pathological Mechanisms

AOC3 exhibits enzymatic activity based on a ping-pong bi-substrate reaction mechanism. In the first step, it oxidizes primary amines to corresponding aldehydes, reducing the enzyme itself; in the second step, the reduced enzyme is reoxidized by molecular oxygen, producing hydrogen peroxide (H₂O₂). This reaction is involved in multiple physiological processes:

• Glucose metabolism regulation: The H₂O₂ generated by AOC3 can mimic insulin activity, promoting the translocation of glucose transporter GLUT4 to the cell membrane and increasing glucose uptake in adipose and muscle cells.
• Amine detoxification: AOC3 catalyzes the oxidative deamination of endogenous and exogenous amines (e.g., microbial metabolites from the gut), preventing their toxic accumulation.
• Extracellular matrix modulation: The aldehydes generated in the reaction can participate in collagen and elastin cross-linking, affecting vascular wall integrity.

AOC3 is most abundantly expressed in adipose tissue, suggesting a special role in adipose metabolism. During adipocyte differentiation, AOC3 expression is significantly upregulated, and the H₂O₂ produced activates the PPARγ signaling pathway to promote adipogenesis. In obesity, AOC3 expression in adipose tissue further increases, forming a pathological positive feedback loop.

Adhesive Function and Inflammatory Regulation

Beyond its enzymatic activity, AOC3 also acts as an adhesion molecule and plays a critical role in inflammatory responses. In the early stages of inflammation, AOC3 mediates specific binding between lymphocytes and vascular endothelium, facilitating their transendothelial migration into inflamed tissues. This process involves several molecular events:

1. Initial rolling: Sialyl Lewis X (sLeX) antigens on leukocyte surfaces bind to AOC3, slowing down leukocyte rolling.
2. Firm adhesion: AOC3 interacts with receptors on lymphocytes, stabilizing adhesion.
3. Transendothelial migration: AOC3 modulates the distribution of junctional proteins, promoting leukocyte extravasation.

In chronic inflammatory models such as rheumatoid arthritis and inflammatory bowel disease, inhibiting AOC3 enzymatic activity or blocking its adhesive function significantly reduces inflammatory cell infiltration and tissue damage. These dual functions position AOC3 as a key link between metabolism and inflammation.

Role in Pathological Processes

In diabetic vascular complications, AOC3 plays a complex role. On one hand, the H₂O₂ generated by its enzymatic activity exacerbates vascular injury under persistent hyperglycemia through:

• Enhanced oxidative stress: H₂O₂ reacts with superoxide to form highly reactive hydroxyl radicals, oxidizing LDL and promoting foam cell formation.
• Accelerated formation of advanced glycation end-products (AGEs): Aldehydes react with protein amines to form AGE precursors.
• Endothelial dysfunction: Aldehyde products directly damage endothelial cells and reduce nitric oxide (NO) bioavailability.

Figure 1. AOC3 is mobilized to the endothelial lumen in response to inflammation, where MMPs cleave and release a soluble, enzymatically active form. (Boyer DS, et al., 2021)

On the other hand, increased endothelial expression of AOC3 is considered an early marker of diabetic microvascular complications such as nephropathy and retinopathy. Clinical studies have shown that serum soluble AOC3 (sVAP-1) levels are significantly elevated in patients with type 2 diabetes and positively correlate with the urinary albumin-to-creatinine ratio, suggesting its potential as a biomarker for diabetic nephropathy progression.

In neurodegenerative diseases, the amine oxidase activity of AOC3 is closely associated with cerebral amyloid angiopathy (CAA). The aldehydes produced by AOC3 facilitate β-amyloid (Aβ) cross-linking and deposition, accelerating amyloid accumulation in cerebral vessel walls. Furthermore, upregulated expression of AOC3 in blood-brain barrier endothelial cells promotes leukocyte infiltration into the brain, exacerbating neuroinflammation.

Translational Research and Clinical Prospects

Given its dual functionality, multiple types of AOC3 inhibitors have been developed:

• Irreversible inhibitors: e.g., hydrazine derivatives (BTT-2052), which covalently bind to the TPQ cofactor and permanently inactivate the enzyme.
• Reversible competitive inhibitors: e.g., imidazoline compounds (PXS-4728A), which occupy the catalytic site.
• Monoclonal antibodies: e.g., anti-AOC3 antibodies (BTT-1003), which block adhesion function without affecting enzymatic activity.

In a Phase II clinical trial, PXS-4728A (an oral, AOC3-specific inhibitor) showed favorable outcomes in patients with non-alcoholic steatohepatitis (NASH). After 24 weeks of treatment, serum ALT levels significantly decreased, liver fat content was reduced (assessed by MRI-PDFF), and no serious adverse effects were observed. These findings support the therapeutic potential of AOC3 inhibition in fatty liver disease.

In inflammatory diseases, the anti-AOC3 monoclonal antibody BTT-1003 improved Disease Activity Score 28 (DAS28) in Phase I/II trials for rheumatoid arthritis. Importantly, this treatment does not compromise baseline immune function and selectively targets pathological inflammation, demonstrating the advantage of tissue-specific immune modulation.

Serum levels of soluble AOC3 (sVAP-1) are gaining recognition as diagnostic biomarkers for various diseases. In diabetic complications, sVAP-1 levels positively correlate with the progression of diabetic nephropathy and rise before microalbuminuria appears. A prospective cohort study revealed that diabetic patients with baseline sVAP-1 >600 ng/mL had a 3.5-fold increased risk of developing overt nephropathy within five years.

In oncology, sVAP-1 has emerged as a promising biomarker for hepatocellular carcinoma (HCC). Studies show that median sVAP-1 levels in HCC patients (950 ng/mL) are significantly higher than in cirrhotic controls (520 ng/mL) and healthy individuals (220 ng/mL). The sensitivity and specificity for HCC diagnosis are 82% and 75%, respectively, and sVAP-1 provides added value in detecting AFP-negative HCC cases.