SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis.

Xiyu Zhang, Cuiting Zheng, Zhenqiang Gao, Hongyu Chen, Kai Li, Lingling Wang, Yuanyuan Zheng, Chunjia Li, Hongjia Zhang, Ming Gong, Hongbing Zhang, Yan Meng

Cardiovascular drugs and therapy 2022 Jun

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Systemic hypertension may induce adverse hypertrophy of the left cardiac ventricle. Pathological cardiac hypertrophy is a common cause of heart failure. We investigated the significance of ferroptosis repressor xCT in hypertrophic cardiomyopathy. xCT expression in angiotensin II (Ang II)-treated mouse hearts and rat cardiomyocytes was determined using qRT-PCR and Western blotting. Cardiac hypertrophy was induced by Ang II infusion in xCT knockout mice and their wildtype counterparts. Blood pressure, cardiac pump function, and pathological changes of cardiac remodeling were analyzed in these mice. Cell death, oxidative stress, and xCT-mediated ferroptosis were examined in Ang II-treated rat cardiomyocytes. After Ang II infusion, xCT was downregulated at day 1 but upregulated at day 14 at both mRNA and protein levels. It was also decreased in Ang II-treated cardiomyocytes, but not in cardiofibroblasts. Inhibition of xCT exacerbated cardiomyocyte hypertrophy and boosted the levels of ferroptosis biomarkers Ptgs2, malondialdehyde, and reactive oxygen species induced by Ang II, while overexpression of xCT opposed these detrimental effects. Furthermore, knockout of xCT aggravated Ang II-mediated mouse cardiac fibrosis, hypertrophy, and dysfunction. Ferrostatin-1, a ferroptosis inhibitor, alleviated the exacerbation of cardiomyocyte hypertrophy caused by inhibiting xCT in cultured rat cells or ablating xCT in mice. xCT acts as a suppressor in Ang II-mediated cardiac hypertrophy by blocking ferroptosis. Positive modulation of xCT may therefore represent a novel therapeutic approach against cardiac hypertrophic diseases. © 2021. Springer Science+Business Media, LLC, part of Springer Nature.

Citation

Xiyu Zhang, Cuiting Zheng, Zhenqiang Gao, Hongyu Chen, Kai Li, Lingling Wang, Yuanyuan Zheng, Chunjia Li, Hongjia Zhang, Ming Gong, Hongbing Zhang, Yan Meng. SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis. Cardiovascular drugs and therapy. 2022 Jun;36(3):437-447