Department of Medicine, Faculty of Medicine, Laval University, Quebec QC, Canada.
Respir Res. 2011 Sep 27;12(1):128. doi: 10.1186/1465-9921-12-128.
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis.
We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis.
We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.
肺动脉高压（PAH）是一种血管重构疾病，其特征在于肺动脉平滑肌细胞（PASMC）的增殖增强和凋亡抑制。这种表型与上调癌蛋白生存素有关，生存素促进线粒体膜电位超极化（减少凋亡），上调生长因子和细胞因子，如血小板衍生生长因子（PDGF）、白细胞介素-6（IL-6）和血管活性物质内皮素-1（ET-1），促进 PASMC 增殖。Krüppel 样因子 5（KLF5）是一种锌指型转录因子，参与细胞分化、增殖、迁移和凋亡的调节。最近的研究表明，KLF5 参与了心血管疾病中的组织重构，如动脉粥样硬化、再狭窄和心肌肥厚。然而，KLF5 在肺动脉高压（PAH）中的作用尚不清楚。我们假设 KLF5 在 PAH 中的上调触发了 PASMC 的增殖和抗凋亡。
我们表明，与对照组相比，KFL5 在人肺活检和从 PAH 患者远端肺动脉分离的培养人 PASMC 中均上调。通过刺激实验，我们证明 PDGF、ET-1 和 IL-6 可在对照组 PASMC 中触发 KLF-5 激活，达到与 PAH-PASMC 中所见相似的水平。STAT3 通路的抑制可阻断 PAH-PASMC 中的 KLF5 激活。一旦被激活，KLF5 可促进细胞周期蛋白 B1 的上调，并促进 PASMC 增殖，并触发生存素表达，使线粒体膜电位超极化，降低 PASMC 凋亡的能力。
我们首次证明 KLF5 在人 PAH 中被激活，并参与了 PAH-PASMC 的促增殖和抗凋亡表型。我们相信，我们的发现将为 KLF5 在 PAH 中的作用开辟新的研究途径，并可能导致新的治疗靶点的确定。
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