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 vessels. We have chosen to focus on the potential of oxidized low density lipoprotein (oxLDL), an important atherogenic agent, to alter sarcoplasmic reticulum (SR) structure and function. Vascular smooth muscle cells (VSMCs) were exposed for 1 to 6 days to low concentrations of minimally oxidized LDL. ATP was used to probe SR function in VSMCs. ATP can increase [Ca(2+)](i) in control VSMCs because of a release of Ca(2+) from the SR. However, after chronic exposure to oxLDL, cells lose their ability to increase [Ca(2+)](i) in response to ATP. These cells also exhibit a depressed rise in [Ca(2+)](i) after exposure to ryanodine. These effects were associated with a decreased immunoreactivity for the ryanodine-sensitive Ca(2+)-release channels in the SR of oxLDL-treated cells. Immunohistochemical analysis of aortic sections obtained from rabbits fed a cholesterol-supplemented diet revealed a significant decrease in the immunoreactivity for ryanodine channels in the plaque and in the medial layer underlying the plaque. In summary, our data identify oxLDL as a component within the atherosclerotic milieu capable of inducing a decrease in smooth muscle ryanodine channel density. This alteration is associated with a significant defect in the ability of the SR within the smooth muscle cell to regulate Ca(2+). These lesions may contribute to the altered vasoreactivity exhibited by atherosclerotic vessels.
Massaeli
H
H
Division of Stroke and Vascular Disease, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Austria
J A
JA
Pierce
G N
GN
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009994:Osmolar Concentration; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism* / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D002791:Cholesterol, Dietary; D019332:Endothelin-1; D007473:Ion Channels; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D012433:Ryanodine; D000255:Adenosine Triphosphate; D002118:Calcium