Angiotensin II (AngII) is a key mediator of the renin-angiotensin system and plays an important role in the regulation of cardiac electrophysiology by affecting various cardiac ion currents, including transient outward potassium current I_to. AngII receptors and molecular components of I_to, K_v4.2 and K_v4.3 channels, have been linked to caveolae structures. However, their functional interaction as well as the importance of such proximity within 50-100nm caveolar nanodomains, remain unknown. To address this, we studied the mechanisms of I_to regulation by AngII in atrial myocytes of wild type (WT) and cardiac-specific caveolin-3 (Cav3) conditional knock-out (Cav3KO) mice. We showed that in WT atrial myocytes, a short-term (2 hours) treatment with AngII (5 µM) significantly reduced I_to density. This effect was prevented (1) by a 30-min pretreatment with a selective antagonist of AngII receptor 1 (Ang1R) losartan (2 µM) or (2) by a selective inhibition of protein kinase C (PKC) by BIM1 (10 µM). The effect of AngII on I_to was completely abolished in Cav3-KO mice, with no change in a baseline I_to current density. In WT atria, Ang1Rs co-localized with Cav3, and the expression of Ang1Rs was significantly decreased in Cav3KO in comparison with WT mice while no change in K_v4.2 and K_v4.3 protein expression was observed. Overall, our findings demonstrate that Cav3 is involved in the regulation of Ang1R expression and is required for modulation of I_to by AngII in mouse atrial myocytes.

中文翻译：

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Caveolin-3 是血管紧张素 II 调节小鼠心房肌细胞瞬时外向钾电流所必需的


血管紧张素II（AngII）是肾素-血管紧张素系统的关键介质，通过影响各种心脏离子电流（包括瞬时外向钾电流I_至） ，在心脏电生理调节中发挥重要作用。 AngII 受体和 I _to 、K _v 4.2 和 K _v 4.3 通道的分子成分与小凹结构有关。然而，它们的功能相互作用以及 50-100nm 凹穴纳米域内这种接近的重要性仍然未知。为了解决这个问题，我们研究了野生型 (WT) 和心脏特异性小窝蛋白 3 (Cav3) 条件敲除 (Cav3KO) 小鼠心房肌细胞中 AngII_调节I 的机制。我们发现，在 WT 心房肌细胞中，用 AngII (5 µM) 进行短期（2 小时）处理可显着降低 I_密度。这种效应可以通过 (1) 使用 AngII 受体 1 (Ang1R) 选择性拮抗剂氯沙坦 (2 µM) 进行 30 分钟预处理或 (2) 通过 BIM1 (10 µM) 选择性抑制蛋白激酶 C (PKC) 来预防。在 Cav3-KO 小鼠中，AngII 对 I _to的影响完全消除，基线 I _to电流密度没有变化。在WT小鼠心房中，Ang1Rs与Cav3共定位，并且与WT小鼠相比，Cav3KO中Ang1Rs的表达显着降低，而K _v 4.2和K _v 4.3蛋白表达没有变化。总体而言，我们的研究结果表明，Cav3 参与 Ang1R 表达的调节，并且是小鼠心房肌细胞中 AngII 调节 I_至所必需的。