Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Life Sci. 2018 Sep 1;208:87-95. doi: 10.1016/j.lfs.2018.07.018. Epub 2018 Jul 17.
It has been shown that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Meanwhile, activation of nuclear factor-kappaB (NF-κB) has been found to induce autophagy in several types of human diseases including cancer and cardiac diseases. However, it is still unknown whether NF-κB mediates autophagy activation in PAH, and whether activation of adenosine monophosphate-activated protein kinase (AMPK) benefits PAH by modulation of NF-κB and autophagy.
Rat models of PAH were established by intraperitoneally injection of monocrotaline (MCT). The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and percentage of medial wall thickness (%MT) were performed to evaluate the development of PAH. The translocation of NF-κB p65 from cytosol to nucleus, the protein levels of LC3A, LC3B, and RND3 were determined by immunoblotting. Metformin was used to activate AMPK.
NF-κB and autophagy were significantly activated in MCT-induced PAH rats, this was accompanied with the reduction of RND3. Pharmacological inhibition of NF-κB suppressed MCT-induced activation of autophagy and down-regulation of RND3 expression and reduced RVSP, RVHI, and %MT in MCT-induced PAH rats. In addition, activation of AMPK by metformin suppressed NF-κB-mediated autophagy activation and down-regulation of RND3 and therefore reduced RVSP, RVHI, and %MT in MCT-induced PAH.
NF-κB-induced autophagy activation and consequent down-regulation of RND3 contributes to the development of PAH in MCT-treated rats. Activation of AMPK prevents the development of PAH by targeting on NF-κB to suppress autophagy and vascular remodeling.
研究表明自噬的激活参与了肺动脉高压（PAH）的发生发展。同时，核因子-κB（NF-κB）的激活已被发现可诱导包括癌症和心脏疾病在内的多种人类疾病的自噬。然而，NF-κB 是否介导 PAH 中的自噬激活，以及腺苷单磷酸激活蛋白激酶（AMPK）的激活是否通过调节 NF-κB 和自噬来有益于 PAH，目前尚不清楚。
通过腹腔注射野百合碱（MCT）建立 PAH 大鼠模型。通过右心室收缩压（RVSP）、右心室肥厚指数（RVHI）和中膜厚度百分比（%MT）评估 PAH 的发生发展。通过免疫印迹法测定 NF-κB p65 从细胞质向细胞核的易位、LC3A、LC3B 和 RND3 的蛋白水平。二甲双胍用于激活 AMPK。
NF-κB 和自噬在 MCT 诱导的 PAH 大鼠中显著激活，同时 RND3 减少。NF-κB 的药物抑制抑制了 MCT 诱导的自噬激活和 RND3 表达的下调，并降低了 MCT 诱导的 PAH 大鼠的 RVSP、RVHI 和 %MT。此外，二甲双胍通过激活 AMPK 抑制 NF-κB 介导的自噬激活和 RND3 的下调，从而降低了 MCT 诱导的 PAH 大鼠的 RVSP、RVHI 和 %MT。
NF-κB 诱导的自噬激活和随后的 RND3 下调导致 MCT 处理的大鼠 PAH 的发生发展。AMPK 的激活通过靶向 NF-κB 抑制自噬和血管重塑，预防 PAH 的发生。
