Lesions in ryanodine channels in smooth muscle cells exposed to oxidized low density lipoprotein

The purpose of the present investigation was to investigate the subcellular basis responsible for the loss of vasoreactivity in atherosclerotic vessel s. We have chosen to focus on the potential of oxidized low density lipopro tein (oxLDL), an important atherogenic agent, to alter sarcoplasmic reticul um (SR) structure and function. Vascular smooth muscle cells (VSMCs) were e xposed for 1 to 6 days to low concentrations of minimally oxidized LDL. ATP was used to probe SR function in VSMCs. ATP can increase [Ca2+](i) in cont rol VSMCs because of a release of Ca2+ from the SR. However, after chronic exposure to oxLDL, cells lose their ability to increase [Ca2+](i) in respon se to ATP. These cells also exhibit a depressed rise in [Ca2+](i) after exp osure to ryanodine, These effects were associated with a decreased immunore activity for the ryanodine-sensitive Ca2+-release channels in the SR of oxL DL-treated cells. Immunohistochemical analysis of aortic sections obtained from rabbits fed a cholesterol-supplemented diet revealed a significant dec rease in the immunoreactivity for ryanodine channels in the plaque and in t he medial layer underlying the plaque. In summary, our data identify oxLDL as a component within the atherosclerotic milieu capable of inducing a decr ease in smooth muscle ryanodine channel density. This alteration is associa ted with a significant defect in the ability of the SR within the smooth mu scle cell to regulate Ca2+. These lesions may contribute to the altered vas oreactivity exhibited by atherosclerotic vessels.