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

PLoS One. 2016 Apr 4;11(4):e0152758. doi: 10.1371/journal.pone.0152758. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors
  • Amine Oxidase (Copper-Containing) / genetics
  • Amine Oxidase (Copper-Containing) / metabolism*
  • Animals
  • Atherosclerosis / chemically induced
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Female
  • Macrophages / enzymology
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Monocytes / enzymology
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Plaque, Atherosclerotic / chemically induced
  • Plaque, Atherosclerotic / enzymology*
  • Plaque, Atherosclerotic / genetics
  • Plaque, Atherosclerotic / pathology
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism

Substances

  • Cell Adhesion Molecules
  • Dietary Fats
  • Receptors, LDL
  • Amine Oxidase (Copper-Containing)
  • semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (31400768/81470564 (YZ); 31200672/31370871 (JW); 31071046 (YY), Jiangsu Natural Science Foundation (BK20130339 (YZ)), Jiangsu Provincial Special Program of Medical Science (BL2012004/BL2014051(YZ); BL2014035 (YY)), Changzhou Applied Basic Science Project (CJ20140059 (YP), and a project (JW and YZ) funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.