Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) K_ATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knockin mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved by genetic downregulation of K_ATP channel activity specifically in VSM, and by chronic administration of the clinically used K_ATP channel inhibitor, glibenclamide. These findings demonstrate that VSM K_ATP channel GoF underlies CS cardiac enlargement and that CS-associated abnormalities are reversible, and provide evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.

中文翻译：

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格列本脲可逆转由 KATP 通道过度活跃引起的 Cantu 综合征心血管异常

Cantu 综合征 (CS) 是一种由ABCC9和KCNJ8中的功能获得性 (GoF) 突变引起的复杂疾病，它们分别编码血管平滑肌 (VSM) K _ATP通道的 SUR2 和 Kir6.1 亚基。CS包括扩张的脉管系统、显着的心脏肥大和其他心血管异常。目前尚无靶向治疗，心血管特征一旦出现是否可以逆转尚不清楚。_{在 CS 敲入小鼠模型中使用转基因和药理学相结合的方法，我们已经证明，通过基因下调特别是在 VSM 中的 K ATP}通道活性以及通过长期施用临床使用的 K _ATP可以实现血管和心脏表型的逆转通道抑制剂格列本脲。这些发现表明 VSM K _ATP通道 GoF 是 CS 心脏扩大的基础，并且 CS 相关异常是可逆的，并提供了格列本脲作为 CS 治疗剂的体内功效的证据。