Reduced membrane cholesterol after chronic hypoxia limits Orai1-mediated pulmonary endothelial Ca2+ entry

American Journal of Physiology. Heart and Circulatory Physiology
Bojun ZhangThomas C Resta

Abstract

Endothelial dysfunction in chronic hypoxia (CH)-induced pulmonary hypertension is characterized by reduced store-operated Ca2+ entry (SOCE) and diminished Ca2+-dependent production of endothelium-derived vasodilators. We recently reported that SOCE in pulmonary arterial endothelial cells (PAECs) is tightly regulated by membrane cholesterol and that decreased membrane cholesterol is responsible for impaired SOCE after CH. However, the ion channels involved in cholesterol-sensitive SOCE are unknown. We hypothesized that cholesterol facilitates SOCE in PAECs through the interaction of Orai1 and stromal interaction molecule 1 (STIM1). The role of cholesterol in Orai1-mediated SOCE was initially assessed using CH exposure in rats (4 wk, 380 mmHg) as a physiological stimulus to decrease PAEC cholesterol. The effects of Orai1 inhibition with AnCoA4 on SOCE were examined in isolated PAEC sheets from control and CH rats after cholesterol supplementation, substitution of endogenous cholesterol with epicholesterol (Epichol), or vehicle treatment. Whereas cholesterol restored endothelial SOCE in CH rats, both Epichol and AnCoA4 attenuated SOCE only in normoxic controls. The Orai1 inhibitor had no further effect in cells pretreated with Epi...Continue Reading

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Citations

Dec 21, 2018·Antioxidants & Redox Signaling·Laura Weise-CrossNikki L Jernigan
Sep 25, 2019·Biomolecules·Louise Conrard, Donatienne Tyteca
Jun 14, 2018·Physiology·Baptiste RodeChristelle Guibert
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Nov 19, 2019·Frontiers in Physiology·Juan Pablo Zuniga-Hertz, Hemal H Patel
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May 21, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Patrick Kwabena OduroQilong Wang

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Methods Mentioned

BETA
proximity ligation assay
confocal microscopy
transfection
proximity ligation
PAECs

Software Mentioned

ImageJ

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