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

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...

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Published in:	Cell stem cell 2022-05, Vol.29 (5), p.840-855.e7
Main Authors:	Xu, Xinxiu, Jin, Kang, Bais, Abha S., Zhu, Wenjuan, Yagi, Hisato, Feinstein, Timothy N., Nguyen, Phong K., Criscione, Joseph D., Liu, Xiaoqin, Beutner, Gisela, Karunakaran, Kalyani B., Rao, Krithika S., He, Haoting, Adams, Phillip, Kuo, Catherine K., Kostka, Dennis, Pryhuber, Gloria S., Shiva, Sruti, Ganapathiraju, Madhavi K., Porter, George A., Lin, Jiuann-Huey Ivy, Aronow, Bruce, Lo, Cecilia W.
Format:	Article
Language:	eng
Subjects:	antioxidant response Antioxidants - metabolism congenital heart disease endoplasmic reticulum stress Heart Defects, Congenital - metabolism heart failure Heart Failure - metabolism Humans hypoplastic left heart syndrome Induced Pluripotent Stem Cells induced pluripotent stem-cell-derived cardiomyocytes Mitochondrial Permeability Transition Pore Myocytes, Cardiac - metabolism Oxidative Stress sildenafil TUDCA
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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. [Display omitted] •Patient iPSC-derived cardiomyocytes were used to model clinical heart failure•Heart failure is linked to mitochondrial defects, redox stress, and apoptosis•Failed antioxidant response is associated with heart failure outcome•Sildenafil or TUDCA rescued uncompensated redox stress, suggesting possible therapy Xu et al. demonstrated feasibility of modeling early heart failure using induced pluripotent stemcell-derived cardiomyocytes from patients with HLHS. 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.
ISSN:	1934-5909 1875-9777