Hypercholesterolemia induces up-regulation of K ACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ

Wu Deng, Anna N. Bukiya, Aldo A. Rodríguez-Menchaca, Zhe Zhang, Clive M. Baumgarten, Diomedes E. Logothetis, Irena Levitan, Avia Rosenhouse-Dantsker

Research output: Contribution to journalArticle

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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 AChcurrents (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.

Original languageEnglish (US)
Pages (from-to)4925-4935
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number7
DOIs
StatePublished - Feb 10 2012

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Phosphatidylinositols
Hypercholesterolemia
Up-Regulation
Cholesterol
Cardiac Myocytes
Nutrition
Diet
Xenopus
Muscle Cells
Modulators
Oocytes
Rodentia
Cardiovascular Diseases
Heart Rate
Chemical activation
Rabbits

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hypercholesterolemia induces up-regulation of K ACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ. / Deng, Wu; Bukiya, Anna N.; Rodríguez-Menchaca, Aldo A.; Zhang, Zhe; Baumgarten, Clive M.; Logothetis, Diomedes E.; Levitan, Irena; Rosenhouse-Dantsker, Avia.

In: Journal of Biological Chemistry, Vol. 287, No. 7, 10.02.2012, p. 4925-4935.

Research output: Contribution to journalArticle

Deng, W, Bukiya, AN, Rodríguez-Menchaca, AA, Zhang, Z, Baumgarten, CM, Logothetis, DE, Levitan, I & Rosenhouse-Dantsker, A 2012, 'Hypercholesterolemia induces up-regulation of K ACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ', Journal of Biological Chemistry, vol. 287, no. 7, pp. 4925-4935. https://doi.org/10.1074/jbc.M111.306134
Deng, Wu ; Bukiya, Anna N. ; Rodríguez-Menchaca, Aldo A. ; Zhang, Zhe ; Baumgarten, Clive M. ; Logothetis, Diomedes E. ; Levitan, Irena ; Rosenhouse-Dantsker, Avia. / Hypercholesterolemia induces up-regulation of K ACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 7. pp. 4925-4935.
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