Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension
Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension
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DOI：
10.1093/cvr/cvy016
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发表时间：
2018-05-01
影响因子：
10.8
通讯作者：
Antigny, Fabrice
中科院分区：
文献类型：
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作者：
Lambert, Melanie;Boet, Angele;Antigny, Fabrice
在肺动脉高压（PAH）患者中发现了编码外向整流K+通道的KCNK3基因突变，并构成了PAH中第一个被描述的通道病变。在人类PAH和实验性肺动脉高压（PH）中，我们证明了KCNK3在肺血管细胞中的表达和功能严重降低，在形态学和血流动力学水平上促进PH样表型。由于KCNK3通道也在人类和啮齿动物心脏中表达，我们旨在阐明KCNK3通道在与ph相关的右心室肥厚（RVH）中的病理生理作用。方法和结果使用全细胞膜片钳技术，我们证明与左心室心肌细胞相比，KCNK3在成年大鼠右心室心肌细胞中主要表达，并参与右心室动作电位的复极期。我们发现，在RVH发生之前，KCNK3功能降低，肺血管阻力增加。在几种PH大鼠模型（暴露于单氯乙酸、慢性缺氧和Sugen/缺氧）和慢性右心室压力过载（肺动脉束带）中，在RVH的发展过程中，右心室心肌细胞的KCNK3功能严重降低。在实验PH中，我们发现在肺血管阻力升高和RVH发生之前，KCNK3功能降低。与非PAH患者相比，PAH患者的人RV组织中KCNK3 mRNA水平也有所降低。与这些发现一致，用特异性抑制剂（A293）慢性抑制大鼠的KCNK3诱导右心室肥大，这与胎儿基因的重新表达、右心室纤维化、右心室炎症以及随后的右心室功能丧失有关。结论KCNK3功能和表达的缺失是与PH相关的右心室肥大/功能障碍的标志。
Aims Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH.Methods and results Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the reexpression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography.Conclusion Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.