Published online before print March 23, 2006, doi: 10.1161/01.RES.0000218776.87842.43
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Submitted on October 19, 2005
Revised on February 7, 2006
Accepted on March 9, 2006
Hypercholesterolemia Suppresses Inwardly Rectifying K+ Channels in Aortic Endothelium In Vitro and In Vivo
Yun Fang ;
From the Institute for Medicine and Engineering (Y.F., E.H., P.F.D., I.L.), Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; Department of Medicine (E.R.M., H.O., S.M.H., R.L.W.), Cardiovascular Division, Section of Vascular Medicine, University of Pennsylvania, Philadelphia; and Department of Pediatrics (G.H.R.), The Children’s Hospital of Philadelphia, Pennsylvania.
* To whom correspondence should be addressed. E-mail: levitan{at}uic.edu.
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.
Key words: K channels • cholesterol • lipoproteins • flow • vasodilatation
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