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SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis
Xiyu Zhang1, Cuiting Zheng1, Zhenqiang Gao1
1Department of Pathology, Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, China.
Insights
The ferroptosis repressor xCT suppresses cardiac hypertrophy by blocking ferroptosis. Modulating xCT offers a potential new therapy for hypertrophic cardiomyopathy and related heart failure conditions.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Molecular Cardiology
Background:
- Systemic hypertension can lead to adverse left ventricular hypertrophy, a precursor to heart failure.
- Understanding the molecular mechanisms underlying pathological cardiac hypertrophy is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of the ferroptosis repressor xCT in the context of hypertrophic cardiomyopathy.
- To determine if xCT expression is altered during angiotensin II-induced cardiac hypertrophy.
Main Methods:
- Assessed xCT expression in mouse hearts and rat cardiomyocytes using qRT-PCR and Western blotting after angiotensin II (Ang II) treatment.
- Induced cardiac hypertrophy in xCT knockout and wildtype mice via Ang II infusion, analyzing hemodynamic and pathological parameters.
- Examined cell death, oxidative stress, and ferroptosis in Ang II-treated rat cardiomyocytes.
Main Results:
- Angiotensin II downregulated xCT in cardiomyocytes, while xCT knockout exacerbated Ang II-induced cardiac hypertrophy, fibrosis, and dysfunction.
- Inhibition of xCT heightened ferroptosis biomarkers and Ang II-induced hypertrophy, whereas xCT overexpression had protective effects.
- Ferrostatin-1, a ferroptosis inhibitor, ameliorated hypertrophy exacerbation caused by xCT inhibition or ablation.
Conclusions:
- xCT functions as a suppressor of Ang II-mediated cardiac hypertrophy by inhibiting ferroptosis.
- Upregulating xCT presents a promising therapeutic strategy for treating cardiac hypertrophic diseases.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
