Vascular Adhesion Protein-1 (VAP-1)/Semicarbazide-Sensitive Amine Oxidase (SSAO): A Potential Therapeutic Target for Atherosclerotic Cardiovascular Diseases

Abstract

Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO), whose enzymatic activity regulates the adhesion/exudation of leukocytes in/from blood vessels. Due to its abundant expressions in vascular systems and prominent roles in inflammations, increasing attentions have been paid to the roles of VAP-1/SSAO in atherosclerosis, a chronic vascular inflammation that eventually drives clinical cardiovascular events. Clinical studies have demonstrated a potential value of soluble VAP-1 (sVAP-1) for the diagnosis and prognosis of cardiovascular diseases. Recent findings revealed that VAP-1 is expressed in atherosclerotic plaques and treatment with VAP-1 inhibitors alleviates the progression of atherosclerosis. This review will focus on the roles of VAP-1/SSAO in the progression of atherosclerotic lesions and therapeutic potentials of VAP-1 inhibitors for cardiovascular diseases.

Keywords: VAP-1; atherosclerosis; inflammation; myocardial infarction; stroke.

FIGURE 1

The involvement of VAP-1 in atherosclerosis. LDL retention and endothelial dysfunction are the essential initiators of atherosclerosis. The vascular inflammation induces the translocation of VAP-1 onto the luminal surface of endothelium, which subsequently interacts with Siglec-9/10 (sialic acid-binding immunoglobulin-like lectin 9/10) to mediate the infiltrations of monocytes into atherosclerotic lesions. Meanwhile, enzymatic products of VAP-1, such as H₂O₂, may further increase the expression of VAP-1 on endothelium and the subsequent transmigration of monocytes. The inflammatory early lesions stimulate the transformation of SMCs in media from the quiescent “contractile” phenotype state to the active “synthetic” state with increased proliferation, migration, and collagen synthesis. VAP-1 in the plasma membrane of SMCs may inhibit their phenotypic switch by its enzymatic products and thereby limit the growth of fibrous cap composed of SMCs and collagens. VAP-1 thus represents a pathological factor for plaque instability characterized by thin fibrous cap overlying a large lipid core rich in mon/macrophage-derived foam cells.