Decrease in pH strongly enhances binding of native, proteolyzed, lipolyzed, and oxidized low density lipoprotein particles to human aortic proteoglycans.
Binding of low density lipoprotein (LDL) to proteoglycans and modification of LDL are key processes in atherogenesis. Recently, it has been demonstrated that during atherogenesis the extracellular pH of atherosclerotic lesions decreases. We have examined the effect of the decreased pH on the binding of LDL to human aortic proteoglycans. The binding of native, oxidized, proteolyzed (alpha-chymotrypsin-treated), or lipolyzed (sphingomyelinase- or phospholipase A(2)-treated) LDL particles to proteoglycans were measured in microtiter well assays at pH 5.5-7.5. We found that the lower the pH, the higher the amount of binding of LDL to proteoglycans. At the lowest pH tested (pH 5.5), the amounts of proteoglycan-bound native, proteolyzed, sphingomyelinase-, and phospholipase A(2)-treated LDL were 20-, 23-, 30-, and 37-fold higher, respectively, than at pH 7.5. Interestingly, although oxidized LDL failed to bind to proteoglycans at neutral pH, there was significant binding at acidic pH. Binding of native and modified LDL to proteoglycans at pH 5.5 was blocked by 1 m NaCl, indicating that at neutral pH LDL binds to proteoglycans via ionic interactions. Inhibition of this binding by acetylation and cyclohexanedione treatment of LDL showed that the positively charged amino acids of apolipoprotein B-100, lysine, and arginine, respectively, mediated the ionic interaction. Taken together, our results suggest that in areas of atherosclerotic arterial intima where the extracellular pH decreases, retention of LDL by proteoglycans is enhanced, leading to extracellular accumulation of LDL and progression of the disease.
Sneck
Mia
M
Wihuri Research Institute, Helsinki, Finland.
Kovanen
Petri T
PT
Oörni
Katariina
K
D001011:Aorta / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008066:Lipolysis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism
D008077:Lipoproteins, LDL; D011509:Proteoglycans; C099252:oxidized low density lipoprotein