Large-Conductance Calcium-Activated Potassium Channel Opener, NS1619, Protects Against Mesenteric Artery Remodeling Induced by Agonistic Autoantibodies Against the Angiotensin II Type 1 Receptor.
Large-Conductance Calcium-Activated Potassium Channel Opener, NS1619, Protects Against Mesenteric Artery Remodeling Induced by Agonistic Autoantibodies Against the Angiotensin II Type 1 Receptor.
复制标题
大电导钙激活钾通道开放剂 NS1619 可防止血管紧张素 II 1 型受体激动性自身抗体诱导的肠系膜动脉重塑
DOI：
10.1161/jaha.121.024046
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发表时间：
2022-02-15
影响因子：
5.4
通讯作者：
Liu, Huirong
中科院分区：
文献类型：
--
作者：
Wang, Meili;Yin, Xiaochen;Li, Shuanglei;Zhang, Xi;Yi, Ming;He, Chunyu;Li, Xiaoyue;Wang, Wei;Zhang, Suli;Liu, Huirong
抗血管紧张素 II 1 型受体 (AT1-AAs) 的激动性自身抗体广泛存在于高血压患者中，并已被证明在血管重塑的病理生理过程中发挥着至关重要的作用。然而，治疗选择是有限的。大电导钙激活钾（BK）通道是血管张力和结构的关键调节剂和潜在治疗靶点。我们之前观察到 AT1-AA 对 BK 通道有抑制作用。然而，BK 通道功能障碍是否参与 AT1-AAs 诱导的血管重塑以及 BK 通道开放剂的治疗效果尚不清楚。在我们的研究中，AT1-AAs 阳性大鼠的肠系膜动脉表现出壁厚度增加、小动脉腔变窄以及胶原蛋白积累增加。膜片钳测试结果显示，AT1-AAs 阳性大鼠肠系膜小动脉平滑肌细胞 BK 通道的电压敏感性下降。使用新鲜分离的肠系膜小动脉平滑肌细胞进行的实验表明，AT1-AA 降低了 BK 通道的开放概率、开放水平、开放停留时间和钙敏感性。用 GFP-ZERO-BK α 亚基质粒转染的 HEK293T 细胞进行的实验表明，存在 BK 通道 α 亚基依赖性机制。 BK通道α亚基缺陷，即KCNMA1−/−大鼠表现出肠系膜动脉重塑表型。 NS1619（一种针对 α 亚基的特异性 BK 通道开放剂）的施用逆转了培养的肠系膜小动脉平滑肌细胞中 AT1-AA 诱导的表型转变和迁移。最后，灌注 NS1619 显着缓解了 AT1-AAs 在体内引起的病理效应。总之，我们提供了令人信服的证据，证明 BK 通道 α 亚基功能障碍介导 AT1-AAs 诱导的肠系膜动脉重塑。保留 BK 通道活性可能作为治疗 AT1-AAs 诱导的适应不良阻力动脉重塑的潜在策略。
Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1‐AAs) extensively exist in patients with hypertensive diseases and have been demonstrated to play crucial roles in the pathophysiological process of vascular remodeling. However, the treatment options are limited. The large‐conductance calcium‐activated potassium (BK) channel is a critical regulator and potential therapeutic target of vascular tone and architecture. We have previously observed that AT1‐AAs have an inhibitory effect on BK channels. However, whether BK channel dysfunction is involved in AT1‐AAs‐induced vascular remodeling and the therapeutic effect of BK channel opener is unclear. In our study, mesenteric arteries from AT1‐AAs‐positive rats exhibited increased wall thickness, narrowing of the arteriolar lumen, and increased collagen accumulation. Patch clamp test results showed that the voltage sensitivity of BK channel declined in mesenteric arteriolar smooth muscle cells from AT1‐AAs‐positive rats. Experiments with freshly isolated mesenteric arteriolar smooth muscle cells showed that AT1‐AAs reduced the opening probability, open levels, open dwell time, and calcium sensitivity of BK channel. Experiments with HEK293T cells transfected with GFP‐ZERO‐BK α‐subunit plasmids suggested a BK channel α‐subunit‐dependent mechanism. BK channel α‐subunit deficient, namely KCNMA1 −/− rats showed a phenotype of mesenteric artery remodeling. The administration of NS1619, a specific BK channel opener targeting the α‐subunit, reversed the phenotypic transition and migration induced by AT1‐AAs in cultured mesenteric arteriolar smooth muscle cells. Finally, perfusion of NS1619 significantly relieved the pathological effects induced by AT1‐AAs in vivo. In summary, we provide compelling evidence that BK channel α‐subunit dysfunction mediates AT1‐AAs‐induced mesenteric artery remodeling. Preservation of BK channel activity may serve as a potential strategy for the treatment of AT1‐AAs‐induced maladaptive resistance artery remodeling.