Cardiovascular consequences of KATP overactivity in Cantu syndrome
Cardiovascular consequences of KATP overactivity in Cantu syndrome
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DOI：
10.1172/jci.insight.121153
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发表时间：
2018-08-09
期刊：
影响因子：
8
通讯作者：
Nichols, Colin G.
中科院分区：
文献类型：
--
作者：
Huang, Yan;McClenaghan, Conor;Nichols, Colin G.
Cantu综合征（CS）的特征是多种血管和心脏异常，包括血管扩张和迂曲、全身性低血压和心脏肥大。这种疾病是由编码孔形成（Kir6.1，KCNJ 8）和辅助（SUR 2，ABCC 9）ATP敏感性钾（K-ATP）通道亚基的基因中的功能获得性（GOF）突变引起的。然而，对分子功能障碍与观察到的复杂病理生理学之间的联系了解甚少，并且没有已知的治疗方法，这在很大程度上是由于缺乏适当的临床前疾病模型来测试治疗。值得注意的是，Kir6.1和SUR 2的表达并不完全重叠，K-ATP GOF在各种心血管组织中的相对贡献仍有待阐明。为了研究CS的病理生理机制，我们使用CRISPR/Cas9工程化将CS相关的SUR 2 [A478 V]和Kir6.1[V65 M]突变引入小鼠中的等同内源性基因座。与人类CS相似，这两种动物都表现出低全身血压和扩张的顺应性血管，以及显著的心脏增大，V65 M动物的影响比A478 V动物更严重。在这两种动物中，全细胞膜片钳记录显示血管平滑肌的基础K-ATP电导增强，解释了血管舒张和血压降低，并证明了CS病因学中平滑肌K-ATP功能障碍的重要作用。超声心动图证实两只动物的原位心脏扩大和心输出量增加。膜片钳记录显示A478 V心室肌细胞K-ATP通道的ATP敏感性降低，但V65 M的ATP敏感性正常，表明心脏重塑继发于心脏外K-ATP过度活动。因此，这些SUR 2 [A478 V]和Kir6.1[V65 M]动物重申了在人类CS中观察到的关键心血管特征。他们建立了由SUR 2/Kir6.1依赖性K-ATP GOF引起的平滑肌兴奋性降低的病理生理学后果的分子基础，并提供了一种经验证的动物模型，用于检查治疗CS的潜在治疗方法。
Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (K-ATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of K-ATP GOF in various cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice. Mirroring human CS, both of these animals exhibit low systemic blood pressure and dilated, compliant blood vessels, as well dramatic cardiac enlargement, the effects being more severe in V65M animals than in A478V animals. In both animals, whole-cell patch-clamp recordings reveal enhanced basal K-ATP conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure, and demonstrating a cardinal role for smooth muscle K-ATP dysfunction in CS etiology. Echocardiography confirms in situ cardiac enlargement and increased cardiac output in both animals. Patch-clamp recordings reveal reduced ATP sensitivity of ventricular myocyte K-ATP channels in A478V, but normal ATP sensitivity in V65M, suggesting that cardiac remodeling occurs secondary to K-ATP overactivity outside of the heart. These SUR2[A478V] and Kir6.1[V65M] animals thus reiterate the key cardiovascular features seen in human CS. They establish the molecular basis of the pathophysiological consequences of reduced smooth muscle excitability resulting from SUR2/Kir6.1-dependent K-ATP GOF, and provide a validated animal model in which to examine potential therapeutic approaches to treating CS.