Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.
Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.
复制标题
在 iPSC 衍生的先天性心脏病模型中，未代偿的线粒体氧化应激是心力衰竭的基础。
DOI：
10.1016/j.stem.2022.03.003
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发表时间：
2022-05-05
期刊：
影响因子：
23.9
通讯作者：
Lo, Cecilia W.
中科院分区：
文献类型：
--
作者：
Xu, Xinxiu;Jin, Kang;Bais, Abha S.;Zhu, Wenjuan;Yagi, Hisato;Feinstein, Timothi N.;Nguyen, Phong K.;Criscione, Joseph D.;Liu, Xiaoqin;Beutner, Gisela;Karunakaran, Kalyani B.;Rao, Krithika S.;He, Haoting;Adams, Philips;Kuo, Catherine K.;Kostka, Dennis;Pryhober, Gloria S.;Shiva, Sruti;Ganapathiraju, Madhavi K.;Porter, George A.;Ivy-Lin, Jiuann-Huey;Aronow, Bruce;Lo, Cecilia W.
左心发育不全综合征(HLHS)是一种严重的先天性心脏病，出生后一年内30%的死亡率死于心力衰竭(HF)，但早期心力衰竭的原因尚不清楚。HLHS患者诱导的多能干细胞来源的心肌细胞(IPSC-CM)显示，早期心力衰竭与细胞凋亡增加、线粒体呼吸缺陷、线粒体通透性转换孔(MPTP)异常开放和抗氧化反应失败所致的氧化还原应激有关。相比之下，没有早期心力衰竭的患者的IPSC-CM显示出正常的呼吸和更高的抗氧化反应。单细胞转录学证实，早期心衰与线粒体功能障碍伴随内质网(ER)应激有关。这些发现表明，未补偿的氧化应激是HLHS早期心力衰竭的基础。重要的是，用西地那非抑制MPTP开放或用TUDCA抑制内质网应激可以挽救线粒体呼吸缺陷、氧化应激和细胞凋亡。总之，这些发现指出了患者IPSC-CM在临床心力衰竭建模和治疗学发展中的潜在用途。Xu等人。证明了使用患者诱导的多能干细胞来源的心肌细胞来模拟早期心力衰竭的可行性。他们观察到，心力衰竭与细胞凋亡增加、线粒体功能障碍、氧化还原和内质网应激有关，所有这些都可以通过西地那非或TUDCA挽救，这表明了治疗的潜力。
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early-HF remains unknown. HLHS patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early-HF showed normal respiration with elevated antioxidant response. Single cell transcriptomics confirmed early HF is associated with mitochondrial dysfunction accompanied by endoplasmic reticulum (ER) stress. These findings indicate uncompensated oxidative stress underlies early-HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics. Xu et al. demonstrated feasibility of modeling early heart failure using patient induced pluripotent stem cell derived cardiomyocytes. They observed that heart failure is linked to increased apoptosis, mitochondrial dysfunction, redox and endoplasmic reticulum stress, all of which were rescued by Sildenafil or TUDCA, suggesting potential for therapy.
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