Deficiency of zinc finger protein 36 exacerbates sepsis-induced cardiomyopathy by activating ferroptosis.

Abstract

Ferroptosis is an important pathological factor in sepsis-induced cardiomyopathy (SIC). Zinc finger protein 36 (ZFP36) is an RNA-binding protein regulating cellular biological processes by degrading target genes. Studies have shown that ZFP36 is highly associated with ferroptosis. BALB/c mice were administered lipopolysaccharide (LPS) intraperitoneally to establish an SIC model. After LPS exposure for 24 h, mice showed myocardial damage and ferroptosis, and an elevated protein level of ZFP36 was detected in the myocardium. H9c2 cells were transfected with plasmid-carrying short hairpin RNA to knock down ZFP36. The mRNA-sequencing data suggested that ZFP36 may be involved in the ferroptosis process of SIC. After inhibiting ZFP36 expression, H9c2 cell viability was reduced, and we detected an increase in lipid peroxides by C11-BODIPY581/591. ZFP36 knockdown intensified LPS-induced ferroptosis and cell injury. ZFP36 expression was inhibited in mice by recombination adeno-associated virus 9-containing shRNA. SIC mice with ZFP36 knockdown showed left ventricular systolic dysfunction aggravatingly. In SIC mice with ZFP36 knockdown, disruption of myocardial structure and increased immunological infiltration. After ZFP36 downregulation, the SIC hearts displayed massive 4-HNE and malondialdehyde accumulation, decreased glutathione content and superoxide dismutase activity, and elevated iron-positive myocardium by Prussian blue staining. The alteration of ferroptosis markers evidenced the activation of ferroptosis in ZFP36-deficient SIC mice. In addition, we observed that the level of solute carrier family 7 member 11 was downregulated after the ZFP36 knockdown both in vivo and in vitro. In conclusion, deficiency of ZFP36 exacerbates SIC by activating ferroptosis.