title: Hypercholesterolemia induces up-regulation of KACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ.
abstract: Hypercholesterolemia is a well-known risk factor for cardiovascular disease. In the heart, activation of K(ACh) mediates the vagal (parasympathetic) negative chronotropic effect on heart rate. Yet, the effect of cholesterol on K(ACh) is unknown. Here we show that cholesterol plays a critical role in modulating K(ACh) currents (I(K,ACh)) in atrial cardiomyocytes. Specifically, cholesterol enrichment of rabbit atrial cardiomyocytes led to enhanced channel activity while cholesterol depletion suppressed I(K,ACh). Moreover, a high-cholesterol diet resulted in up to 3-fold increase in I(K,ACh) in rodents. In accordance, elevated currents were observed in Xenopus oocytes expressing the Kir3.1/Kir3.4 heteromer that underlies I(K,ACh). Furthermore, our data suggest that cholesterol affects I(K,ACh) via a mechanism which is independent of both PI(4,5)P(2) and Gβγ. Interestingly, the effect of cholesterol on I(K,ACh) is opposite to its effect on I(K1) in atrial myocytes. The latter are suppressed by cholesterol enrichment and by high-cholesterol diet, and facilitated following cholesterol depletion. These findings establish that cholesterol plays a critical role in modulating I(K,ACh) in atrial cardiomyocytes via a mechanism independent of the channel's major modulators.
authors.affiliation: Department of Medicine, Pulmonary Section, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Deng
authors.forename: Anna N
authors.initials: AN
authors.lastname: Bukiya
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rodríguez-Menchaca
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Clive M
authors.initials: CM
authors.lastname: Baumgarten
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.forename: Irena
authors.initials: I
authors.lastname: Levitan
authors.forename: Avia
authors.initials: A
authors.lastname: Rosenhouse-Dantsker
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D015854:Up-Regulation; D014982:Xenopus laevis
chemical_list: D004041:Dietary Fats; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D002784:Cholesterol