PINK1/Parkin Deficiency Enhances Vascular Remodeling and Aggravates Hypoxia-induced Pulmonary Hypertension.

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rakhshinda Rehman, Paul Dieffenbach, Shamsudheen K Vellarikkal, Alexis M Corcoran, Leilani Pomales, Antonio Arciniegas Rubio, Katherin Zambrano-Vera, Fotios Spyropoulos, Kosmas Kosmas, Hillaire Lam, Harilaos Filippakis, Mark A Perrella, Laura E Fredenburgh, Helen Christou
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引用次数: 0

Abstract

Alterations in mitochondrial structure and function contribute to vascular smooth muscle cell (VSMC) phenotypic switching and are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. The PINK1/Parkin-mediated mitophagy pathway is a key mitochondrial quality control program by which defective mitochondria are targeted for removal. The role of PINK1/Parkin-mediated mitophagy in VSMC phenotypic switching and PAH pathogenesis is not known. We sought to evaluate if PINK1/Parkin-induced mitophagy modulates VSMC phenotypic switching and contributes to PAH. Mitophagy and PINK1/Parkin expression were evaluated in human PAH lungs and Pulmonary Artery Smooth Muscle Cells (PASMCs). PINK1 and Parkin were silenced in human and mouse primary PASMCs and global PINK1 and Parkin knockout mice were used. After silencing of PINK1 and Parkin, PASMC proliferation and apoptosis were measured, and experimental pulmonary hypertension was evaluated after exposure to hypoxia. Parkin and PINK1 levels were reduced in the pulmonary vasculature or PASMCs from PAH lungs, accompanied by decreased mitophagy. PINK1 and Parkin knockout animals had an exaggerated pulmonary hypertension phenotype upon exposure to hypoxia. Genetic silencing of PINK1 and Parkin in human and mouse PASMCs led to increased proliferation and apoptosis resistance. We conclude that Reduced PINK1/Parkin-induced mitophagy contributes to pulmonary artery smooth muscle cell phenotypic switching and exacerbates PAH.

PINK1/Parkin缺乏增强血管重塑,加重缺氧引起的肺动脉高压。
线粒体结构和功能的改变有助于血管平滑肌细胞(VSMC)表型转换,并与肺动脉高压(PAH)发病机制有因果关系。PINK1/ parkin介导的线粒体自噬途径是一个关键的线粒体质量控制程序,通过该程序,有缺陷的线粒体被靶向去除。PINK1/ parkin介导的线粒体自噬在VSMC表型转换和PAH发病机制中的作用尚不清楚。我们试图评估PINK1/帕金森诱导的线粒体自噬是否调节VSMC表型转换并有助于PAH。在人PAH肺和肺动脉平滑肌细胞(PASMCs)中检测线粒体自噬和PINK1/Parkin的表达。PINK1和Parkin在人和小鼠原代PASMCs中被沉默,并使用全局PINK1和Parkin敲除小鼠。在沉默PINK1和Parkin后,检测PASMC的增殖和凋亡,并评估缺氧暴露后的实验性肺动脉高压。PAH肺血管或PASMCs中的Parkin和PINK1水平降低,并伴有线粒体自噬减少。PINK1和Parkin基因敲除动物暴露于缺氧时肺动脉高压表型夸张。人类和小鼠PASMCs中PINK1和Parkin的基因沉默导致细胞增殖和细胞凋亡抵抗增加。我们得出结论,PINK1/ parkin诱导的线粒体自噬减少有助于肺动脉平滑肌细胞表型转换并加剧PAH。
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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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