Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity Conor
Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity Conor
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DOI：
10.1172/jci130571
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发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Nichols, Colin G.
中科院分区：
文献类型：
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作者：
McClenaghan, Conor;Huang, Yan;Nichols, Colin G.
坎图综合征是一种由ABCC9和KCNJ8基因突变引起的复杂疾病，这两个基因分别编码血管平滑肌(VSM)K-ATP通道的SUR2和Kir6.1亚基。CS包括血管扩张、明显的心肌肥厚和其他心血管异常。目前还没有针对性的治疗方法，而且尚不清楚心血管功能一旦显露出来是否可以逆转。利用转基因和药理学相结合的方法，在CS敲打小鼠模型中，我们已经证明，血管和心脏表型的逆转可以通过遗传下调VSM中的K-ATP通道活性，以及通过长期使用临床使用的K-ATP通道抑制剂格列本脲来实现。这些发现表明VSM K-ATP通道Gof是CS心脏增大的基础，CS相关的异常是可逆的，并为格列本脲作为CS治疗药物的体内疗效提供了证据。
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.