We found previously that KLF4 expression was up‐regulated in cultured rat and human pulmonary artery smooth muscle cells (PASMCs) exposed to cigarette smoke (CS) extract and in pulmonary artery from rats with pulmonary hypertension induced by CS. Here, we aim to investigate whether CS‐induced pulmonary hypertension (PH) is prevented and ameliorated by targeted pulmonary vascular gene knockdown of KLF4 via adeno‐associated virus 1 (AAV1)‐KLF4‐shRNA in vivo in rat model. The preventive and therapeutic effects were observed according to the different time‐point of AAV1‐KLF4‐shRNA intratracheal administration. We tested haemodynamic measurements of systemic and pulmonary circulations and observed the degree of pulmonary vascular remodelling. In the preventive experiment, KLF4 expression and some pulmonary circulation hemodynamic measurements such as right ventricular systolic pressure (RVSP), mean right ventricular pressure (mRVP), peak RV pressure rate of rise (dP/dt max) and right ventricle (RV) contractility index were increased significantly in the CS‐induced PH model. While in the prevention group (AAV1‐KLF4‐shRNA group), RVSP, mRVP, dP/dt max and RV contractility index which are associated with systolic function of right ventricle decreased and the degree of pulmonary vascular remodelling relieved. In the therapeutic experiment, we observed a similar trend. Our findings emphasize the feasibility of sustained pulmonary vascular KLF4 gene knockdown using intratracheal delivery of AAV1 in an animal model of cigarette smoke‐induced PH and determined gene transfer of KLF4‐shRNA could prevent and ameliorate the progression of PH.

中文翻译：

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AAV1-KLF4-shRNA对吸烟所致肺动脉高压的预防和治疗作用


我们之前发现，在暴露于香烟烟雾（CS）提取物的培养大鼠和人肺动脉平滑肌细胞（PASMC）以及由CS诱导的肺动脉高压大鼠的肺动脉中，KLF4表达上调。在这里，我们的目的是研究在大鼠模型体内通过腺相关病毒 1 (AAV1)-KLF4-shRNA 靶向肺血管基因敲低 KLF4 是否可以预防和改善 CS 诱导的肺动脉高压 (PH)。根据AAV1-KLF4-shRNA气管内给药的不同时间点观察其预防和治疗效果。我们测试了全身循环和肺循环的血流动力学测量，并观察了肺血管重塑的程度。在预防性实验中，KLF4表达和一些肺循环血流动力学测量，例如右心室收缩压（RVSP）、平均右心室压力（mRVP）、右心室压力峰值上升率（dP/dt max）和右心室（RV）收缩力在 CS 诱导的 PH 模型中，指数显着增加。而预防组（AAV1-KLF4-shRNA组）与右心室收缩功能相关的RVSP、mRVP、dP/dt max和RV收缩指数降低，肺血管重构程度减轻。在治疗实验中，我们观察到类似的趋势。我们的研究结果强调了在香烟烟雾诱导的肺动脉高压动物模型中使用气管内递送 AAV1 持续敲低肺血管 KLF4 基因的可行性，并确定 KLF4-shRNA 的基因转移可以预防和改善肺动脉高压的进展。