Silent inward rectifier K+ channels in hypercholesterolemia.

Hypercholesterolemia is an independent risk factor for development of cardiovascular disease1 and has been demonstrated to impair endothelium-dependent and independent vasodilatation.2 However, the mechanisms responsible for changes in vascular reactivity and impaired blood flow regulation induced by hypercholesterolemia remain unclear. Previous studies in cultured endothelial cells have shown that cholesterol impairs whole-cell KIR currents.3 Levitan and colleagues4 in this issue of Circulation Research extend these findings to show that exposure of endothelial cells to pathophysiologically relevant concentrations of acetylated low density lipoprotein (LDL) or very low density lipoprotein (vLDL) leads to membrane cholesterol enrichment, and also inhibits endothelial KIR channel currents and shear stress–induced activation of these channels. More importantly, the authors show, for the first time, that in freshly isolated endothelial cells from hypercholesterolemic pigs, KIR channel currents are impaired, and that this inhibition can be reversed by methyl-cyclodextrin. Thus, hypercholesterolemia can be added to the list of pathophysiological states that appear to inhibit the function of vascular KIR channels, including hypertension and diabetes.5 What remains unclear is the mechanism by which elevated membrane cholesterol silences endothelial KIR channels, the generality of these findings to KIR channels expressed in vascular smooth muscle cells, and the significance of cholesterol modulation of endothelial or smooth muscle KIR channels in resistance arteries and arterioles, vessels that participate in the regulation of blood pressure and blood flow. A number of ion channels, in addition to KIR channels,6 appear to associate with cholesterol-rich lipid rafts, and changes in membrane cholesterol content have been shown to modulate the function of several ion channels.7,8 However, the mechanisms responsible for targeting channels to lipid rafts and how cholesterol modulates channel function have not been established. Endothelial cells appear to express predominantly Kir 2.1 and 2.2 KIR channels.9 When expressed in Chinese hamster ovary (CHO) cells, these channels show similar sensitivity to membrane cholesterol as native endothelial KIR channels.6 Furthermore, in this expression system, cholesterol-induced changes in whole-cell KIR channel currents are not affected by inhibition of protein synthesis, and are not associated with changes in cell surface expression of Kir 2.X channels, nor in the single channel currents through these channels.6 These data suggest that cholesterol-induced changes in KIR channel currents do not involve alterations in channel expression, trafficking, or modulation of single channel conductance, activation or inactivation kinetics.6 Instead, cholesterol seems to cause Kir 2.X channel to become “silent”. Interestingly, Kir2.3 channel proteins are less sensitive to cholesterol than other Kir2.X family members,6 which may provide a molecular clue to the identity of the portion of these channels involved in modulation by cholesterol. Vascular smooth muscle cells also express Kir2.1 channels that importantly determine the reactivity of vessels to changes in extracellular K , and may be involved in functional regulation of blood flow in tissues such as the heart and the brain.10 Cholesterol appears to exert similar effects on native Kir 2.X channels expressed in endothelial cells and channels expressed in CHO cells.6 Thus, it seems likely that hypercholesterolemia also may impact smooth muscle KIR channels and potentially profoundly affect the regulation of vascular smooth muscle tone independent from, or in addition to, effects on endothelial KIR channels. Although there is considerable experimental evidence supporting a physiological role for KIR channels in vascular smooth muscle cells in the wall of resistance arteries and arterioles, particularly in the brain and heart,10 the functional role of endothelial KIR channels in vessels that impact regulation of blood pressure and blood flow has not been well studied. First, it seems unlikely that endothelial cell KIR channels significantly participate in the regulation of resting endothelial cell membrane potential in resistance arteries and arterioles, because endothelial cell membrane potential in these vessels is approximately 30 mV,11–13 and studies of KIR channel currents in freshly isolated arteriolar endothelial cells (Figure 1) suggest that KIR channels contribute little if any current at this potential.14 However, because of the shape of the current–voltage (I–V) relationship for these channels (Figure 1), and the relatively depolarized membrane potentials in resistance vessels, outward currents through KIR channels may be activated simply by membrane hyperpolarization (Figure 2). Thus, KIR channels may act to amplify hyperpolarization induced by other K channels and may contribute to endothelium-dependent vasodilation (Figure 2).14 This mechanism could provide an explanation for Ba sensitivity of bradykinin-induced dilation reported in human forearm.15 Hyperpolarization-induced activation of currents through endothelial KIR channels also may provide a mechaThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Mich. Correspondence to William F. Jackson, PhD, Department of Pharmacology and Toxicology, Michigan State University, B420 Life Sciences Bldg, East Lansing, MI 48824. E-mail [email protected] (Circ Res. 2006;98:982-984.) © 2006 American Heart Association, Inc.