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Publication of the Month | April 2022

    Home Publication of the Month Publication of the Month | April 2022

    Publication of the Month | April 2022

    By The McGowan Institute For Regenerative Medicine | Publication of the Month, Publication of the Month 2022 | Comments are Closed | 27 April, 2022 | 0

    Author: Xinxiu Xu, Kang Jin, Abha S. Bai, Wenjuan Zhu, Hisato Yagi, Timothy N. Feinstein, Phong K. Nguyen, Joseph D. Criscione, Xiaoqin Liu, Gisela Beutner, Kalyani B. Karunakaran, Krithika S. Rao, Haoting He, Phillip Adams, Catherine K. Kuo, Dennis Kostka, Gloria S. Pryhuber, Sruti Shiva, Madhavi K. Ganapathiraju, George A. Porter Jr., Jiuann-Huey Ivy Lin, Bruce Aronow, Cecilia W. Lo

    Title: Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease

    Summary: 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. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that 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 that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that 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.

    Source: Cell Stem Cell. 2022 Apr 7;S1934-5909(22)00101-1. doi: 10.1016/j.stem.2022.03.003. Online ahead of print.

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