Lipoprotein(a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo(a) transgenic rabbits

Am J Pathol. 2002 Jan;160(1):227-36. doi: 10.1016/S0002-9440(10)64366-0.


Elevated plasma lipoprotein(a) [Lp(a)] levels constitute an independent risk factor for the development of atherosclerosis. However, the mechanism underlying Lp(a) atherogenicity is unclear. Recently, we demonstrated that Lp(a) may potentially be proatherogenic in transgenic rabbits expressing human apolipoprotein(a) [apo(a)]. In this study, we further investigated atherosclerotic lesions of transgenic rabbits by morphometry and immunohistochemistry. On a cholesterol diet, human apo(a) transgenic rabbits had more extensive atherosclerotic lesions of the aorta, carotid artery, iliac artery, and coronary artery than did nontransgenic littermate rabbits as defined by increased intimal lesion area. Enhanced lesion development in transgenic rabbits was characterized by increased accumulation of smooth muscle cells, that was often associated with the Lp(a) deposition. To explore the possibility that Lp(a) may be involved in the smooth-muscle cell phenotypic modulation, we stained the lesions using a panel of monoclonal antibodies against smooth-muscle myosin heavy-chain isoforms (SM1, SM2, and SMemb) and basic transcriptional element binding protein-2 (BTEB2). We found that a large number of smooth muscle cells located in the apo(a)-containing areas of transgenic rabbits were positive for SMemb and BTEB2, suggesting that these smooth muscle cells were either immature or in the state of activation. In addition, transgenic rabbits showed delayed fibrinolytic activity accompanied by increased plasma plasminogen activator inhibitor-1. We conclude that Lp(a) may enhance the lesion development by mediating smooth muscle cell proliferation and dedifferentiation possibly because of impaired fibrinolytic activity.

MeSH terms

  • Animals
  • Animals, Genetically Modified / genetics
  • Apolipoproteins A / genetics
  • Apolipoproteins A / pharmacology
  • Apolipoproteins A / physiology*
  • Arteriosclerosis / blood
  • Arteriosclerosis / pathology*
  • Arteriosclerosis / physiopathology*
  • Cell Differentiation / physiology
  • Cell Division / physiology
  • Female
  • Fibrinolysis / drug effects
  • Humans
  • Immunohistochemistry / methods
  • Lipids / blood
  • Lipoprotein(a) / physiology*
  • Lipoproteins / blood
  • Male
  • Muscle, Smooth, Vascular / pathology*
  • Plasminogen / metabolism
  • Plasminogen Activator Inhibitor 1 / blood
  • Rabbits
  • Staining and Labeling
  • Transforming Growth Factor beta / metabolism


  • Apolipoproteins A
  • Lipids
  • Lipoprotein(a)
  • Lipoproteins
  • Plasminogen Activator Inhibitor 1
  • Transforming Growth Factor beta
  • Plasminogen