Membrane cholesterol oxidation downregulates atrial β-adrenergic responses in ROS-dependent manner.,Cellular Signalling

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Membrane cholesterol oxidation downregulates atrial β-adrenergic responses in ROS-dependent manner.
Cellular Signalling ( IF 4.4 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.cellsig.2019.109503
Roman Ursan ₁ , Ulia G Odnoshivkina ₂ , Alexey M Petrov ₃

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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.

中文翻译：

膜胆固醇氧化以ROS依赖性方式下调心房β-肾上腺素反应。

膜胆固醇的氧化是许多病理状况（包括心血管疾病）的标志。胆固醇可能会由于自由基和酶促反应而被氧化。在这里，我们研究了胆固醇氧化酶（ChO）氧化胆固醇对离体小鼠心房中β-AR刺激反应的影响。急性暴露于ChO会导致部分胆固醇氧化，而心房膜胆固醇含量没有明显变化。用ChO本身进行预处理不会影响收缩和Ca2 +瞬时振幅。但是，胆固醇氧化显着抑制了β-AR介导的收缩力和Ca2 +瞬态以及NO水平的增加。同时，ChO明显促进了β-AR诱导的活性氧（ROS）的产生。抗氧化剂和蛋白激酶C抑制剂阻止了ChO对ISO依赖性收缩力，Ca2 +瞬变和NO产生的抑制作用。选择性β2-AR拮抗剂具有相似的作用，该拮抗剂也可抑制ChO预处理后ROS水平的升高。这些结果表明，膜胆固醇氧化可增强依赖于β2-AR的ROS产生，从而抑制β-AR介导的小鼠心房收缩力，Ca2 +瞬变和NO合成的增加。在病理条件下，氧化胆固醇的修饰可能会导致β-AR信号传导紊乱。这些结果表明，膜胆固醇氧化可增强小鼠心房中β2-AR依赖性的ROS生成升高，从而导致β-AR介导的收缩力，Ca2 +瞬变和NO合成增加受到抑制。在病理条件下，氧化胆固醇的修饰可能会导致β-AR信号传导紊乱。这些结果表明，膜胆固醇氧化可增强依赖于β2-AR的ROS产生，从而抑制β-AR介导的小鼠心房收缩力，Ca2 +瞬变和NO合成的增加。在病理条件下，氧化胆固醇的修饰可能会导致β-AR信号传导紊乱。

更新日期：2019-12-17

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