Objective: We have previously described that changes in the expression of Kv channels associate to phenotypic modulation (PM), so that Kv1.3/Kv1.5 ratio is a landmark of vascular smooth muscle cells phenotype. Moreover, we demonstrated that the Kv1.3 functional expression is relevant for PM in several types of vascular lesions. Here, we explore the efficacy of Kv1.3 inhibition for the prevention of remodeling in human vessels, and the mechanisms linking the switch in Kv1.3 /Kv1.5 ratio to PM. Approach and Results: Vascular remodeling was explored using organ culture and primary cultures of vascular smooth muscle cells obtained from human vessels. We studied the effects of Kv1.3 inhibition on serum-induced remodeling, as well as the impact of viral vector-mediated overexpression of Kv channels or myocardin knock-down. Kv1.3 blockade prevented remodeling by inhibiting proliferation, migration, and extracellular matrix secretion. PM activated Kv1.3 via downregulation of Kv1.5. Hence, both Kv1.3 blockers and Kv1.5 overexpression inhibited remodeling in a nonadditive fashion. Finally, myocardin knock-down induced vessel remodeling and Kv1.5 downregulation and myocardin overexpression increased Kv1.5, while Kv1.5 overexpression inhibited PM without changing myocardin expression. Conclusions: We demonstrate that Kv1.5 channel gene is a myocardin-regulated, vascular smooth muscle cells contractile marker. Kv1.5 downregulation upon PM leaves Kv1.3 as the dominant Kv1 channel expressed in dedifferentiated cells. We demonstrated that the inhibition of Kv1.3 channel function with selective blockers or by preventing Kv1.5 downregulation can represent an effective, novel strategy for the prevention of intimal hyperplasia and restenosis of the human vessels used for coronary angioplasty procedures.

中文翻译：

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心肌素依赖性 Kv1.5 通道表达可防止器官培养中人血管的表型调节

客观的：我们之前已经描述过Kv通道表达的变化与表型调节（PM）相关，因此Kv1.3/Kv1.5比率是血管平滑肌细胞表型的标志。此外，我们证明 Kv1.3 功能表达与几种类型的血管病变中的 PM 相关。在这里，我们探讨了 Kv1.3 抑制对于预防人体血管重塑的功效，以及 Kv1.3 /Kv1.5 比率转换与 PM 的联系机制。 方法和结果：使用从人体血管获得的血管平滑肌细胞的器官培养和原代培养物来探索血管重塑。我们研究了 Kv1.3 抑制对血清诱导的重塑的影响，以及病毒载体介导的 Kv 通道过度表达或心肌素敲低的影响。Kv1.3 阻断通过抑制增殖、迁移和细胞外基质分泌来防止重塑。PM 通过下调 Kv1.5 激活 Kv1.3。因此，Kv1.3 阻滞剂和 Kv1.5 过表达均以非累加方式抑制重塑。最后，心肌素敲低诱导血管重塑和 Kv1.5 下调，心肌素过表达增加 Kv1.5，而 Kv1.5 过表达抑制 PM，但不改变心肌素表达。 结论：我们证明 Kv1.5 通道基因是心肌素调节的血管平滑肌细胞收缩标记。PM 上的 Kv1.5 下调使 Kv1.3 成为去分化细胞中表达的主要 Kv1 通道。我们证明，用选择性阻滞剂或通过防止 Kv1.5 下调来抑制 Kv1.3 通道功能可以代表一种有效的新颖策略，用于预防冠状动脉血管成形术中使用的人体血管内膜增生和再狭窄。