Research Article

Concentration Polarization of Ox-LDL and Its Effect on Cell Proliferation and Apoptosis in Human Endothelial Cells

Shijie Liu, Jawahar L Mehta, Yubo Fan, Xiaoyan Deng and Zufeng Ding*

Published: 12/30/2016 | Volume 1 - Issue 1 | Pages: 011-018


Background: Flow-dependent concentration polarization of native LDL is important in the localization of atherogenesis. However, ox-LDL plays a more important role than n-LDL in atherogenesis by inducing cell proliferation and apoptosis. We hypothesized that concentration polarization of ox-LDL may adversely affect vascular beds due to its toxicity to endothelial cell (EC) lining.

Methods: Using a parallel-plate flow chamber technique, we studied water filtration rate and wall concentration of ox-LDLs EC monolayers cultured on permeable or non-permeable membranes. ECs cultured on permeable and non-permeable membranes were examined in terms of cell viability, ox-LDL uptake, LOX-1 expression and cell apoptosis (Cytochrome c and Bcl-2 expression). We observed that the wall concentration of ox-LDL was about 16% higher in the permeable group than in the permeable group (P<0.05). Cell proliferation (MTT assay) increased in response to low concentration of ox-LDL (1-5 μg/ml), and fell drastically in response to higher concentration; all these changes were more pronounced in the permeable group than in the non-permeable group. The uptake of ox-LDL and LOX-1 expression by ECs were also significantly higher in the permeable group than in the non-permeable group of cultured cells.

Conclusions: These observations suggest that concentration polarization of ox-LDL occurs in an artery that is permeable to water, and ox-LDL concentration polarization can enhance ox-LDL accumulation into the arterial wall and accelerate EC proliferation at low concentrations and apoptosis at high concentrations, possibly via LOX-1 expression.

Read Full Article HTML DOI: 10.29328/journal.jccm.1001003 Cite this Article


  1. Chistiakov DA, Melnichenko A A, Orekhov AN, Bobryshev Y V. Paraoxonase and atherosclerosis-related cardiovascular diseases. Biochimie. 2017; 132: 19-27. Ref.:
  2. Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovas Res. 2006; 69: 36-45. Ref.:
  3. Ding Z, Liu S, Wang X, Mathur P, Dai Y, et al. Cross-Talk between PCSK9 and Damaged mtDNA in Vascular Smooth Muscle Cells: Role in Apoptosis. Antioxid Redox Signal. 2016; 25 997-1008. Ref.:
  4. Ding Z, Liu S, Wang X, Deng X, Fan Y, et al. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res. 2015; 107: 556-567. Ref.:  
  5. Chistiakov DA, Orekhov AN, Bobryshev YV. LOX-1-Mediated Effects on Vascular Cells in Atherosclerosis. Cell Physiol Biochem. 2016; 38: 1851-1859. Ref.:
  6. Cobbold CA, Sherratt JA, Maxwell SR. Lipoprotein oxidation and its significance for atherosclerosis: a mathematical approach. Bull Math Biol. 2002; 64: 65-95. Ref.:  
  7. Chen XP, Xun KL, Wu Q, Zhang TT, Shi JS, et al. Oxidized low density lipoprotein receptor-1 mediates oxidized low density lipoprotein-induced apoptosis in human umbilical vein endothelial cells: Role of reactive oxygen species. Vasc Pharmacol. 2007; 47: 1-9. Ref.:
  8. Dimmeler S, Zeiher AM. Endothelial cell apoptosis in angiogenesis and vessel regression. Circ Res. 2000; 87: 434-439. Ref.:
  9. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362: 801-809. Ref.:
  10. Essler M, Retzer M, Bauer M, Heemskerk JW, Aepfelbacher M, et al. Mildly oxidized low density lipoprotein induces contraction of human endothelial cells through activation of Rho/Rho kinase and inhibition of myosin light chain phosphatase. J Biol Chem. 1999; 274: 30361-30364. Ref.:
  11. Zhao B, Ehringer WD, Dierichs R, Miller FN. Oxidized low-density lipoprotein increases endothelial intracellular calcium and alters cytoskeletal F-actin distribution. Eur J Clin Invest. 1997; 27: 48-54. Ref.:
  12. Galle J, Heinloth A, Wanner C, Heermeier K. Dual effect of oxidized LDL on cell cycle in human endothelial cells through oxidative stress. Kidney Int Suppl. 2001; 78: 120-123. Ref.:
  13. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med. 2002; 8: 1249-1256. Ref.:
  14. Ding Z, Liu S, Deng X, Fan Y, Wang X, et al. Hemodynamic shear stress modulates endothelial cell autophagy: Role of LOX-1. Int J Cardiol. 2015; 1: 86-95. Ref.:
  15. Kleinstreuer C, Hyun S, Buchanan JR Jr, Longest PW, Archie JP Jr, et al. Hemodynamic parameters and early intimal thickening in branching blood vessels. Crit Rev Biomed Eng. 2001; 29: 1-64. Ref.:
  16. Ku DN, Giddens DP. Pulsatile flow in a model carotid bifurcation. Arteriosclerosis. 1983; 3: 31-39. Ref.:
  17. Hyun S, Kleinstreuer C, Archie JP Jr. Computational particle-hemodynamics analysis and geometric reconstruction after carotid endarterectomy. Comput Biol Med. 2001; 31: 365-384. Ref.:
  18. Deng X, Marois Y, How T, Merhi Y, King M, et al. Luminal surface concentration of lipoprotein (LDL) and its effect on the wall uptake of cholesterol by canine carotid arteries. J Vasc Surg. 1995; 21: 135-145. Ref.:
  19. Ding Z, Liu S, Wang X, Deng X, Fan Y, et al. Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signal. 2015; 22: 760-771. Ref.:
  20. Hafiane A, Genest J. High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk. BBA Clin. 2015; 31: 175-188. Ref.:
  21. Cominacini L, Garbin U, Davoli A, Micciolo R, Bosello O, et al. A simple test for predisposition to LDL oxidation based on the fluorescence development during copper-catalyzed oxidative modification. J Lipid Res. 1991; 32: 349-358. Ref.:
  22. Ding Z, Liu S, Wang X, Dai Y, Khaidakov M, et al. LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: implications in atherogenesis. Cardiovasc Res. 2014; 103: 619-628. Ref.:
  23. Xavier HT, Abdalla DS, Martinez TL, Ramires JA, Gagliardi AR. Effects of oxidized LDL on in vitro proliferation and spontaneous motility of human coronary artery endothelial cells. Arq Bras Cardiol. 2004; 83: 493-497. Ref.:  
  24. Dandapat A, Hu C, Sun L, Mehta JL. Small concentrations of oxLDL induce capillary tube formation from endothelial cells via LOX-1-dependent redox-sensitive pathway. Arterioscler Thromb Vasc Biol. 2007; 27: 2435-2442. Ref.:
  25. Hoff HF, O'Neil JA. Oxidation of LDL: role in atherogenesis. Klin Wochenschf. 1991; 69: 1032-1038. Ref.:
  26. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997; 386: 73-77. Ref.:
  27. Ding Z, Liu S, Wang X, Khaidakov M, Dai Y, et al. Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis. Sci Rep. 2013; 3: 1077. Ref.:
  28. Moriwaki H, Kume N, Sawamura T, Aoyama T, Hoshikawa H, et al. Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein. Arterioscler Thromb Vasc Biol. 1998; 18: 1541-1547. Ref.: