Kcnk3 功能障碍可加重左心室压力超负荷所致肺动脉高压的发展。
Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload.
机构信息
Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
出版信息
Cardiovasc Res. 2021 Nov 1;117(12):2474-2488. doi: 10.1093/cvr/cvab016.
AIMS
Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown.
METHODS AND RESULTS
We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats.
CONCLUSIONS
Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.
目的
肺动脉高压（PH）是左心疾病（LHD，第 2 组 PH）的常见并发症，可导致右心室（RV）衰竭和死亡。在肺动脉高压（PAH，第 1 组 PH）中已经发现了几个钾离子通道亚家族 K 成员 3（KCNK3）的功能丧失（LOF）突变。此外，我们发现 KCNK3 功能障碍是肺血管和 RV 水平 PAH 的标志。然而，KCNK3 在由 LHD 引起的 PH 的病理生物学中的作用尚不清楚。
方法和结果
我们通过超声心动图、RV 导管插入术、组织学分析和分子生物学实验评估了 KCNK3 在升主动脉缩窄（AAC）诱导的 PH 中的作用，在 WT 和 Kcnk3-LOF 突变大鼠中。我们发现 Kcnk3-LOF 突变对 AAC 引起的左心室（LV）代偿性向心性肥厚的发展没有影响，而左心房排空分数在 AAC-Kcnk3 突变大鼠中受损。AAC 动物（WT 和 Kcnk3 突变大鼠）发生了继发于 AAC 的 PH，并且 Kcnk3 突变大鼠比 WT 大鼠发生了更严重的 PH。AAC-Kcnk3 突变大鼠发生 RV 和 LV 纤维化，与右心室和左心室 Col1a1 mRNA 增加相关。与 AAC-WT 大鼠相比，AAC-Kcnk3 突变大鼠发生严重的肺血管（肺动脉和肺静脉）重塑，伴有强烈的血管周围和支气管周围炎症、血管周围水肿、肺泡壁增厚和肺血管细胞增殖过度。最后，在 AAC-Kcnk3 突变大鼠的肺、RV、LV 和左心房中，我们发现 Il-6 和骨桥蛋白表达的强烈增加以及肺 Ctnnd1 mRNA（编码 p120 连环蛋白）的减少，导致 AAC-Kcnk3 突变大鼠的过度肺和心脏重塑以及肺血管水肿。
结论
我们的结果表明，Kcnk3-LOF 是 AAC 引起 PH 的病理生物学中的关键事件，表明 Kcnk3 通道功能障碍可能在由 LHD 引起的 PH 发展中发挥潜在的关键作用。
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