Angiotensin type 1 and type 2 receptors-induced mitochondrial dysfunction promotes ferroptosis in cardiomyocytes

Hong Fang; Omer Cavdar; Zhiping Yao; Xuewei Zhu; Yi Shen; Chi Liu

doi:10.1038/s41371-024-00982-7

Angiotensin type 1 and type 2 receptors-induced mitochondrial dysfunction promotes ferroptosis in cardiomyocytes

J Hum Hypertens. 2025 Jan 9. doi: 10.1038/s41371-024-00982-7. Online ahead of print.

Authors

Hong Fang^#¹, Omer Cavdar^#¹, Zhiping Yao¹, Xuewei Zhu², Yi Shen³, Chi Liu⁴

Affiliations

¹ Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
² Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University of School Medicine, Winston-Salem, NC, USA.
³ Department of General Practice, Pudong New Area District Zhoupu Hospital, Shanghai, China. [email protected].
⁴ Geriatrics Center & National Clinical Research Center for Aging and Medicine, Jing'an District Central Hospital of Shanghai, Fudan University, Shanghai, China. [email protected].

^# Contributed equally.

PMID: 39789125
DOI: 10.1038/s41371-024-00982-7

Abstract

Previous studies suggest that ferroptosis is involved in cardiovascular diseases. The aim of the present study is to investigate the causal relationship between angiotensin II type 1 and type 2 receptors (AT_1/2R) activities and mitochondrial dysfunction in induction of cardiomyocyte ferroptosis. Human AC16 cardiomyocytes were first pre-treated with an AT_1/2R blockers, before stimulated with angiotensin II (Ang II) for 24 h. The redox status of the cardiomyocytes were assessed by measuring the cellular malondialdehyde (MDA), superoxide dismutase (SOD), and Nicotinamide-adenine dinucleotide phosphate, (NADPH) levels using biochemical methods. Mitochondrial reactive oxygen specifics (mitROS), mitochondrial memebrane potential, and Fe²⁺ levels were determined using flow cytometry. The signaling pathways, including the glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), sirtuin1, and ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) pathways, were evaluated using western blotting. Our results demonstrated that Ang II significantly elevated the levels of MDA, Fe²⁺, mitoROS, and FtMt and markedly reduced SOD, NADPH, mitochondrial membrane potential, GPX4, HO-1, Sirt1, SFXN1, Nrf2, and FSP1 levels in cardiomyocyte, which were reversed by blockade of AT_1/2R. Our results suggest that AT_1/2R signaling can induce myocardial ferroptosis by impairing mitochondrial function via multiple signaling pathways, including the cyst (e)ine /GSH/GPX4 axis and FSP1/coenzyme Q10 (CoQ10) axis.