The preventive and therapeutic effects of AAV1-KLF4-shRNA in cigarette smoke-induced pulmonary hypertension.
The preventive and therapeutic effects of AAV1-KLF4-shRNA in cigarette smoke-induced pulmonary hypertension.
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AAV1-KLF4-shRNA对香烟烟雾性肺动脉高压的防治作用
DOI：
10.1111/jcmm.16194
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Sun D;Ding D;Li Q;Xie M;Xu Y;Liu X
我们先前发现，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）中以及CS诱导的肺动脉高压大鼠的肺动脉中，KLF 4表达上调。在这里，我们的目标是研究在大鼠模型中通过腺相关病毒1（AAV 1）-KLF 4-shRNA体内靶向肺血管基因敲除KLF 4是否可以预防和改善CS诱导的肺动脉高压（PH）。根据AAV 1-KLF 4-shRNA在不同时间点给药，观察其预防和治疗效果。我们测试了体循环和肺循环的血流动力学测量，并观察了肺血管重建的程度。在预防性实验中，在CS诱导的PH模型中，KLF 4表达和一些肺循环血流动力学测量值，如右心室收缩压（RVSP）、平均右心室压（mRVP）、右心室压力峰值上升率（dP/dt max）和右心室（RV）收缩指数显著增加。而预防组（AAV 1-KLF 4-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，我们观察到了类似的趋势。我们的研究结果强调了在香烟烟雾诱导的PH动物模型中使用AAV 1的气管内递送持续肺血管KLF 4基因敲低的可行性，并且确定KLF 4-shRNA的基因转移可以预防和改善PH的进展。
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.
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影响因子：
4.2
作者：
Gubrij, Igor B.;Martin, Sara Rebecca;Johnson, Larry G.
通讯作者：
Johnson, Larry G.
影响因子：
8
作者：
Foster, KW;Liu, ZL;Ruppert, JM
通讯作者：
Ruppert, JM
影响因子：
0.4
作者：
Kuken, B. N.;Aikemu, A. N. W. E.;Wulasihan, M. H. Y. T.
通讯作者：
Wulasihan, M. H. Y. T.
DOI：
10.1016/s0006-291x(03)01356-1
发表时间：
2003-08-22
影响因子：
3.1
作者：
Ohnishi, S;Ohnami, S;Yoshida, T
通讯作者：
Yoshida, T
影响因子：
18.2
作者：
Hulot, Jean-Sebastien;Salem, Joe-Elie;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.