Membrane cholesterol oxidation downregulates atrial β-adrenergic responses in ROS-dependent manner

• Published in: Cellular signalling 2020-03, Vol.67, p.109503-109503, Article 109503
• Main Authors: Ursan, Roman, Odnoshivkina, Ulia G., Petrov, Alexey M.
• Format: Article
• Language: English
• Subjects: Cholesterol; Heart; Nitric oxide; Oxysterols; Reactive oxygen species; β-Adrenoceptors
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2019.109503

Oxidation of membrane cholesterol is a hallmark of many pathological conditions, including cardiovascular diseases. Cholesterol could be oxidized in a result of free radical and enzymatic reactions. Here, we studied the effect of cholesterol oxidation by cholesterol oxidase (ChO) on responses to β-AR stimulation in isolated mouse atria. Acute exposure to ChO led to partial cholesterol oxidation without a significant change in atrial membrane cholesterol content. Pretreatment with ChO itself did not affect contractions and Ca2+ transient amplitude. However, cholesterol oxidation markedly suppressed β-AR-mediated increase in contractility and Ca2+ transient as well as NO levels. At the same time, ChO markedly facilitated β-AR-induced reactive oxygen species (ROS) production. Antioxidant and protein kinase C inhibitor prevented the depressant action of ChO on ISO-dependent contractility, Ca2+ transient and NO production. Similar effects had a selective β2-AR antagonist, which also suppressed the increase in ROS levels after ChO pretreatment. These results suggest that membrane cholesterol oxidation enhances β2-AR-dependent elevation of ROS production, leading to suppression of β-AR-mediated increase in contractility, Ca2+ transient and NO synthesis in mice atria. The oxidative cholesterol modification could contribute to disturbance in β-AR signaling in pathological conditions. [Display omitted] •Cholesterol oxidase (ChO) modifies membrane cholesterol in isolated mice atria.•β-AR stimulation increases contractility, intracellular Ca2+ transient and NO levels.•Oxidation of membrane cholesterol suppresses these effects of β-AR activation.•The depressant action of ChO is linked with upregulation of ROS production.•Cholesterol oxidation increases the ROS production in a β2-AR-dependent manner.