Role of oxidized low density lipoprotein in calcium homeostasis in vascular smooth muscle cells
MetadataShow full item record
Low density lipoprotein (LDL) is an important risk factor for atherosclerotic disease. LDL may be oxidized (oxLDL) by free radicals in a lipid and an aqueous environment. OxLDL plays an important role in atherosclerosis, possibly by altering Ca2+ within vascular smooth muscle cells (VSMC). Acute exposure of VSMC to oxLDL immediately increased [Ca2+] i through an IP3 mediated pathway. However, atherosclerosis is a gradual process in which VSMCs are more likely exposed to low concentrations of oxLDL over extended periods of time rather than acute exposures. It is very possible, therefore, that lower [oxLDL] and longer exposure times may induce a very different response with regard to regulation of [Ca2+ ]i. VSMC incubated with oxLDL (0.001-0.025 mg/ml) for up to 6 days significantly decreased [Ca2+]i transients in response to a variety of inotropic agents. OxLDL did not have a cytotoxic effect. Therefore, we hypothesized that a disruption in the IP 3 or ryanodine dependent release of SR Ca2+ may be the mechanism responsible for this effect. As detected by immunocytochemical analysis chronic exposure of VSMC to oxLDL induced a depression in the density of both IP3 and ryanodine receptors. This trend was also observed in aortic sections from rabbits maintained on a high cholesterol diet. Similar treatment conditions significantly increased the total SERCA2 ATPase content. At higher [oxLDL], we observed a significant loss of myosin and actin as the cell phenotype changed. In addition, these proteins formed giant aggregates which appeared to be in the process of being expelled from the cell. Our data demonstrate, therefore, that the change in Ca2+i is very different depending upon prior exposure of VSMC to oxLDL. The two effects of oxLDL on Ca2+i may play very different but equally important pathogenic roles in atherosclerosis. The acute effects may play an important pathogenic role in the initial atherosclerotic process, the chronic effects of oxLDL may provide a mechanism for the altered vascular tone during atherosclerosis. Furthermore, the process of transforming VSMC into foam cell morphology involves an unusual extrusion mechanism for contractile proteins which was dependent upon oxidation products within the LDL.