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  • Title: Downregulation of the (pro)renin receptor alleviates ferroptosis-associated cardiac pathological changes via the NCOA 4-mediated ferritinophagy pathway in diabetic cardiomyopathy.
    Author: Zhang X, Dong X, Jie H, Li S, Li H, Su Y, Li L, Kang L, Dong B, Zhang Y.
    Journal: Int Immunopharmacol; 2024 Sep 10; 138():112605. PubMed ID: 38963979.
    Abstract:
    Ferroptosis, characterized by the accumulation of reactive oxygen species and lipid peroxidation, is involved in various cardiovascular diseases. (Pro)renin receptor (PRR) in performs as ligands in the autophagic process, and its function in diabetic cardiomyopathy (DCM) is not fully understood. We investigated whether PRR promotes ferroptosis through the nuclear receptor coactivator 4 (NCOA 4)-mediated ferritinophagy pathway and thus contributes to DCM. We first established a mouse model of DCM with downregulated and upregulated PRR expression and used a ferroptosis inhibitor. Myocardial inflammation and fibrosis levels were then measured, cardiac function and ferroptosis-related indices were assessed. In vitro, neonatal rat ventricular primary cardiomyocytes were cultured with high glucose and transfected with recombinant adenoviruses knocking down or overexpressing the PRR, along with a ferroptosis inhibitor and small interfering RNA for the ferritinophagy receptor, NCOA4. Ferroptosis levels were measured in vitro. The results showed that the knockdown of PRR not only alleviated cardiomyocyte ferroptosis in vivo but also mitigated the HG-induced ferroptosis in vitro. Moreover, administration of Fer-1 can inhibit HG-induced ferroptosis. NCOA4 knockdown blocked the effect of PRR on ferroptosis and improved cell survival. Our result indicated that inhibition of PRR and NCOA4 expression provides a new therapeutic strategy for the treatment of DCM. The effect of PRR on the pathological process of DCM in mice may be in promoting cardiomyocyte ferroptosis through the NCOA 4-mediated ferritinophagy pathway.
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