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

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 (ATR) activities and mitochondrial dysfunction in induction of cardiomyocyte ferroptosis. Human AC16 cardiomyocytes were first pre-treated with an ATR 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 Fe 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, Fe, 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 ATR. Our results suggest that ATR 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.