PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway

Abstract

Doxorubicin (DOX), a commonly used antitumor agent, is often accompanied by its dosage-dependent cardiotoxicity, which incorporates ferroptosis in its pathogenesis. Protein arginine methyltransferase 4 (PRMT4) is a transcription regulator involved in the modulation of oxidative stress and autophagy, but its role in DOX-induced cardiomyopathy (DIC) and ferroptosis remains elusive. Herein, we aimed to investigate the involvement and the underlying mechanisms of PRMT4 in the pathogenesis of DIC. Our present study revealed that the expression level of PRMT4 was markedly decreased in DOX-treated cardiomyocytes. Interestingly, it is noted that PRMT4 overexpression accelerated ferroptosis to aggravate DIC, while its gene disruption or pharmaceutical inhibition exhibited the opposite effect. Mechanistically, our observation demonstrated that PRMT4 interacted with the nuclear factor erythroid 2-related factor 2 (Nrf2) to promote its enzymatic methylation, which restricted the nuclear translocation of Nrf2 and subsequently suppressed the transcription of glutathione peroxidase 4 (GPX4). Importantly, the detrimental role of PRMT4 in DOXinduced cardiomyocyte ferroptosis was abolished by Nrf2 activation or Fer-1 administration. Collectively, our data reveal that PRMT4 inhibits Nrf2/GPX4 signaling to accelerate ferroptosis in DIC, suggesting that targeting PRMT4 may present as a potential preventive strategy against the development of DIC.

Relevance of Ferroptosis to Cardiotoxicity Caused by Anthracyclines: Mechanisms to Target Treatments

“…Notably, many of the genes associated with ferroptosis are target genes for Nrf2, but DIC-related studies mainly focus on GPX4 and HO-1 genes. Nrf2 up-regulates the expression of GPX4 and has an anti-ferroptosis effect ( 101 – 103 ). Nrf2 can be methylated by the protein arginine methyltransferase 4 (PRMT4), leading to its nuclear restriction and consequently decreased GPX4 expression.…”

“…Nrf2 can be methylated by the protein arginine methyltransferase 4 (PRMT4), leading to its nuclear restriction and consequently decreased GPX4 expression. PRMT4 aggravated the expression of ferroptosis markers (ROS, MDA, NCO4, and Fe 2+ ) in the DOX-induced primary neonatal rat ventricular myocytes and C57BL/6 J mice cardiotoxicity models, and this influence can be mitigated by PRMT4 knockout ( 103 ). However, studies have also shown that Nrf2-mediated activation of HO-1 promotes ferroptosis.…”

Role of Iron-Related Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Diseases

“…Protein arginine methyltransferase 4 (PRMT4) participates in the regulation of transcription, particularly oxidative stress and autophagy modulation, and can promote ferroptosis during DOX-induced cardiomyopathy by inhibiting Nrf2/GPX4 signaling [ 91 ]. Fisetin, an abundant flavonoid in fruits and vegetables, attenuated DOX-induced cardiomyopathy via the inhibition of ferroptosis by activating SIRT1/Nrf2 signaling [ 92 ].…”

The underlying pathological mechanism of ferroptosis in the development of cardiovascular disease

“…A proteomic analysis showed that GPX4 downregulation using specific siRNA or chemical inhibitor RSL3 caused CMs ferroptosis during MI ( 40 ). Activation of nuclear factor erythroid 2-related factor 2/xCT/GPX4 signaling pathway attenuates CMs ferroptosis in doxorubicin-induced cardiomyopathy and myocardial I/R injury by inhibiting oxidative stress ( 41 , 42 ). Besides, the ferroptosis inhibitor ferrostatin-1 markedly prevented pathological myocardial remodeling and fibrosis in angiotensin II-induced hypertensive cardiomyopathy by attenuating the upregulation of ferrous ion levels and lipid peroxidation in mouse microvascular endothelial cells (ECs) through modulating the xCT/GPX4 signaling ( 43 ).…”