Inactivation of Semicarbazide-Sensitive Amine Oxidase Stabilizes the Established Atherosclerotic Lesions via Inducing the Phenotypic Switch of Smooth Muscle Cells

Abstract

Given that the elevated serum semicarbazide-sensitive amine oxidase (SSAO) activity is associated with the severity of carotid atherosclerosis in clinic, the current study aims to investigate whether SSAO inactivation by semicarbazide is beneficial for established atherosclerotic lesions in LDLr knockout mice on a high-fat/high- cholesterol Western-type diet or after dietary lipid lowering. Despite no impact on plasma total cholesterol levels, the infiltration of circulating monocytes into peripheral tissues, and the size of atherosclerotic lesions, abrogation of SSAO activity resulted in the stabilization of established lesions as evidenced by the increased collagen contents under both conditions. Moreover, SSAO inactivation decreased Ly6Chigh monocytosis and lesion macrophage contents in hypercholesterolemic mice, while no effect was observed in mice after normalization of hypercholesterolemia by dietary lipid lowering. Strikingly, abrogation of SSAO activity significantly increased not only the absolute numbers of smooth muscle cells (SMCs), but also the percent of SMCs with a synthetic phenotype in established lesions of mice regardless of plasma cholesterol levels. Overall, our data indicate that SSAO inactivation in vivo stabilizes the established plaques mainly via inducing the switch of SMCs from a contractile to a synthetic phenotype. Targeting SSAO activity thus may represent a potential treatment for patients with atherosclerosis.

Inhibition of Semicarbazide-sensitive Amine Oxidase Reduces Atherosclerosis in Cholesterol-fed New Zealand White Rabbits

“…In the present study, VAP-1/SSAO inhibition by PXS-4728A significantly reduced atherosclerosis, which was different from previous reports in other animal models 17 , 18 . In LDL receptor knock-out mice, 3 or 6 weeks of SSAO inhibition by semicarbazide after feeding western diet for 6 or 9 weeks promoted the switch of SMC from a contractile phenotype to a synthetic phenotype and increased the accumulation of collagens and the thickness of cap, thereby enhancing plaque stability.…”

“…In LDL receptor knock-out mice, 3 or 6 weeks of SSAO inhibition by semicarbazide after feeding western diet for 6 or 9 weeks promoted the switch of SMC from a contractile phenotype to a synthetic phenotype and increased the accumulation of collagens and the thickness of cap, thereby enhancing plaque stability. However, there was no significant difference in plasma TC and plaque size between the treatment and the placebo group 18 , which was different from the findings of our study. Furthermore, if semicarbazide was administered simultaneously with western diet, it inhibited the migration of circulating monocytes into peripheral tissue and aggravated the development of atherosclerosis 17 .…”

“…So far, literature regarding the effects of VAP-1/SSAO inhibition on atherosclerosis is limited, and the results remain inconsistent. Two studies using semicarbazide to abrogate VAP-1/SSAO activity in LDL receptor knockout mice have demonstrated that VAP-1/SSAO inactivation may aggravate atherosclerotic development through induction of SMC phenotypic switching 17 , whereas it also exerts an anti-atherogenic effect by limiting leukocyte infiltration 18 . Since semicarbazide can also act on enzymes other than VAP-1/SSAO involved in atherogenesis 19 – 24 , off-target effects may explain the conflicting results.…”

Leukocyte trafficking-associated vascular adhesion protein 1 is expressed and functionally active in atherosclerotic plaques

“…Here, we found that treatment with LJP1586 led to a significant reduction in the density of macrophages in atherosclerotic plaques in mice, suggesting that VAP-1 is a potential target for therapeutics aimed at reducing inflammation associated with atherosclerosis. These results are in the line with previous mouse studies using a prototypic SSAO inhibitor, semicarbazide (also inhibiting lysyl oxidases and thus not being specific for VAP-1), as a treatment 29 30 . Mice with pre-existing, advanced atherosclerotic plaques were treated with VAP-1-targeted small molecule LJP1586 that probably explains that the short-term therapy at this stage had no effect on the size/amount of plaques.…”

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

“…So far, there are limited studies that investigate the effects of VAP-1/SSAO inhibition on atherosclerosis. [26][27][28] Two of them used semicarbazide to inhibit VAP-1/SSAO activity in LDL receptor knock-out mice, with conflicting results. In one report, semicarbazide aggravated atherosclerotic lesions.…”