Hypercholesterolemia suppresses inwardly rectifying K+ channels in aortic endothelium in vitro and in vivo.
Inwardly rectifying K+ (Kir) channels are responsible for maintaining endothelial membrane potential and play a key role in endothelium-dependent vasorelaxation. In this study, we show that endothelial Kir channels are suppressed by hypercholesterolemic levels of lipoproteins in vitro and by serum hypercholesterolemia in vivo. Specifically, exposing human aortic endothelial cells to acetylated low-density lipoprotein or very low density lipoprotein resulted in a time- and concentration-dependent decrease in Kir current that correlated with the degree of cholesterol loading. The suppression was fully reversible by cholesterol depletion. Furthermore, a decrease in Kir current resulted in depolarization of endothelial membrane potential. Most important, the flow sensitivity of Kir currents was also impaired by cholesterol loading. Specifically, flow-induced increase in Kir current was suppressed by 70%, and flow-induced hyperpolarization was almost completely abrogated. Furthermore, we show that hypercholesterolemia in vivo also strongly suppresses endothelial Kir currents and causes a shift in endothelial membrane potential, as determined by comparing the currents in aortic endothelial cells freshly isolated from healthy or hypercholesterolemic pigs. Therefore, we suggest that suppression of Kir current is one of the important factors in hypercholesterolemia-induced endothelial dysfunction.
Fang
Yun
Y
Institute for Medicine and Engineering, Department of Pathology and Laboratory Medicine, University of Pennsylvania, USA.
Mohler
Emile R
ER
Hsieh
Esther
E
Osman
Hashim
H
Hashemi
Seyed M
SM
Davies
Peter F
PF
Rothblat
George H
GH
Wilensky
Robert L
RL
Levitan
Irena
I
D000818:Animals; D001011:Aorta; D002784:Cholesterol; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005263:Femoral Artery / Q000503:physiopathology; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009919:Orchiectomy; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D013552:Swine
D024661:Potassium Channels, Inwardly Rectifying; D002784:Cholesterol