Leptin promotes neointima formation and smooth muscle cell proliferation via NADPH oxidase activation and signalling in caveolin-rich microdomains

Cardiovasc Res. 2013 Aug 1;99(3):555-65. doi: 10.1093/cvr/cvt126. Epub 2013 May 30.

Abstract

Aims: Apolipoprotein E (apoE) may act as a vasculoprotective factor by promoting plasma lipid clearance and cholesterol efflux. Moreover, apoE accumulates at sites of vascular injury and modulates the effect of growth factors on smooth muscle cells (SMCs). Experimental data suggested that hypothalamic apoE expression is reduced in obesity and associated with leptin resistance. In this study, we examined the role of apoE in mediating the effects of leptin on vascular lesion formation.

Methods and results: Leptin was administered to apoE knockout (apoE-/-) mice via osmotic pumps to increase its circulating levels. Morphometric analysis revealed that leptin did not alter neointima formation and failed to increase α-actin- or PCNA-immunopositive SMCs after vascular injury. Similar findings were obtained after analysis of atherosclerotic lesions. Comparison of apoE-/-, wild-type, or LDL receptor-/- mice and functional analyses in aortic SMCs from WT or apoE-/- mice or human arterial SMCs after treatment with small interfering (si)RNA or heparinase revealed that leptin requires the presence of apoE, expressed, secreted and bound to the cell surface, to fully activate leptin receptor signalling and to promote SMC proliferation and neointima formation. Mechanistically, leptin induced the phosphorylation and membrane translocation of caveolin (cav)-1, and apoE down-regulation or caveolae disruption inhibited the leptin-induced p47phox activation, ROS formation and SMC proliferation. Finally, leptin failed to increase neointima formation in mice lacking cav-1.

Conclusion: Our findings suggest that apoE mediates the effects of leptin on vascular lesion formation by stabilizing cav-1-enriched cell membrane microdomains in SMCs, thus allowing NADPH oxidase assembly and ROS-mediated mitogenic signalling.

Keywords: Apolipoprotein E; Atherosclerosis; Caveolin-1; Leptin; Neointima; Reactive oxygen species; Smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Caveolin 1 / deficiency
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Humans
  • Leptin / metabolism*
  • Male
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology*
  • NADPH Oxidases / metabolism*
  • Neointima / etiology*
  • Neointima / metabolism*
  • Neointima / pathology
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Signal Transduction

Substances

  • Apolipoproteins E
  • Caveolin 1
  • Leptin
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, LDL
  • NADPH Oxidases