Hypercholesterolemia Induces Up-regulation of KACh Cardiac Currents via a Mechanism Independent of Phosphatidylinositol 4,5-Bisphosphate and Gβγ

Hypercholesterolemia is a well-known risk factor for cardiovascular disease. In the heart, activation of KACh mediates the vagal (parasympathetic) negative chronotropic effect on heart rate. Yet, the effect of cholesterol on KACh is unknown. Here we show that cholesterol plays a critical role in modulating KACh currents (IK,ACh) in atrial cardiomyocytes. Specifically, cholesterol enrichment of rabbit atrial cardiomyocytes led to enhanced channel activity while cholesterol depletion suppressed IK,ACh. Moreover, a high-cholesterol diet resulted in up to 3-fold increase in IK,ACh in rodents. In accordance, elevated currents were observed in Xenopus oocytes expressing the Kir3.1/Kir3.4 heteromer that underlies IK,ACh. Furthermore, our data suggest that cholesterol affects IK,ACh via a mechanism which is independent of both PI(4,5)P2 and Gβγ. Interestingly, the effect of cholesterol on IK,ACh is opposite to its effect on IK1 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 IK,ACh in atrial cardiomyocytes via a mechanism independent of the channel's major modulators. Background: KACh channels play a key role in controlling the heart rate. Results: KACh currents are enhanced by cholesterol enrichment and high cholesterol diet. Conclusion: Cholesterol plays a critical role in modulating IK,ACh in atrial cardiomyocytes. Significance: The increase in IK,ACh following cholesterol enrichment is likely to play a critical role in hypercholesterolemia-induced dysfunction of the heart.