Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

Abstract

Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

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

“…By contrast, in LDLr −/− ApoB 100/100 mice on WTD, Sivola et al demonstrated that 4-weeks treatment with JLP-1586, another VAP-1 inhibitor, had no effect on plaque size, body weight, or plasma lipid levels, but decreased the density of macrophages in atherosclerotic lesions ( Silvola et al, 2016 ). In addition, Wang et al found that ApoE −/− mice or rabbits treated with PXS-4728A, a specific SSAO inhibitor, exhibited reduced atheroma with less oxidative stress and endothelial dysfunction, and markedly alleviated plasma levels of lipids and glucose ( Wang et al, 2018a ; Wang et al, 2018b ). Given that comparable LDL-C/glucose lowering by atorvastatin resulted in a similar reduction of lesions, it seems that the atheroprotective effect of PXS-4728A is largely attributed to the reduced levels of LDL-C/glucose.…”

Diet and Obesity-Induced Methylglyoxal Production and Links to Metabolic Disease

“…Increased metabolic enzyme expression is associated with the development of diabetes and diabetic complications. Enzymes in the SSAO family form MG during amino acid breakdown and are highly expressed in adipose tissue and in endothelial cells. , Inhibiting SSAO enzymes decreased MG levels, protected pancreatic beta-cells, decreased weight gain and fat deposition, and alleviated the symptoms of diabetic complications. − AR forms MG through the polyol pathway and is associated with the development of many diabetic complications; it was first described for its role in causing lens damage . Its inhibition decreased MG levels and the incidence of diabetic complications. ,− Intriguingly, MG increased the expression and activity of AR .…”

Hypercholesterolemia of obese mice with deletion of vascular adhesion protein-1 occurs without other atherosclerosis risk factor

“…First, the mild obesity of these mice strikingly contrasts with the decreased fattening found in rodents treated by pharmacological inhibitors of SSAO, such as hydralazine [49] , a fluoroallylamine derivative [50] , semicarbazide [51] or phenelzine [52,53] . A better understanding of the selectivity of these inhibitors will help to explain these apparent inconsistencies, as all of them have "off-target" actions (for reviews, see [9,54] ). Second, the pharmacological inhibition of VAP-1/SSAO has been reported to be beneficial for experimental atherosclerosis in mice and rabbits [55,56] .…”