Inhibition of the Long non-coding RNA ZFAS1 attenuates pathogenic ferroptosis by sponging miR-150-5p to activate CCND2 against diabetic cardiomyopathy

Abstract

Background Diabetic cardiomyopathy (DCM) needs to be responsible for the increasing morbidity and mortality in diabetic patients with heart failure. Unfortunately, the pathogenesis of DCM has yet to be elaborate. Here we investigate the important role of lncRNA-ZFAS1 in the pathological process of DCM associated with ferroptosis. Methods Microarray data analysis of DCM in the patients or mice model from GEO was presented that ZFAS1 was significantly upregulated, miR-150-5p and CCND2 were significantly downregulated. High glucose (HG)-treated cardiomyocytes and db/db mice were simulated DCM in vitro and in vivo. Ad-ZFAS1, Ad-sh-ZFAS1, mimic miR-150-5p, Ad-CCND2, Ad-sh-CCND2 were injected into mice model or transfected into HG-treated Cardiomyocytes to clarify whether ZFAS1 can regulate miR-150-5p and CCND2 on ferroptosis. Effect of ZFAS1 on the left ventricular myocardial tissues in db/db mice and HG-treated cardiomyocytes, ferroptosis and apoptosis was determined by Masson staining, immunohistochemical staining, western blot, MBB staining, immunofluorescence staining and JC-1staining. The relationship among ZFAS1, miR-150-5p, CCND2 was identified by dual luciferase reporter assay and RNA Pull-down assay. Results Inhibition of ZFAS1 led to the reduced collagen deposition, decreased cardiomyocytes apoptosis, ferroptosis and attenuated the DCM progress. ZFAS1 can sponge miR-150-5p to regulate CCND2 expression. Ad-sh-ZFAS1, miR-150-5p mimic and Ad-CCND2 transfection contributed to attenuate ferroptosis and DCM both in vitro and in vivo, while transfection Ad-ZFAS1could reverse the positive effect of miR-150-5p mimic and Ad-CCND2 both in vitro and in vivo. Conclusion lncRNA-ZFAS1 acted as a ceRNA to sponge miR-150-5p can regulate CCND2 to promote cardiomyocytes ferroptosis and developed DCM, and inhibition of ZFAS1 could be a promising therapeutic target for the treatment and prevention of DCM.

The Emerging Role of Noncoding RNA Regulation of the Ferroptosis in Cardiovascular Diseases

“…Ni et al found that lncRNA-ZFAS1 as a ceRNA sponge miR-150-5p can regulate CCND2, thereby promoting ferroptosis in diabetic cardiomyopathy (DCM). Inhibiting lncRNA-ZFAS1 leads to decreased collagen deposition, decreased cardiomyocyte apoptosis and ferroptosis, and the progress of DCM weakened [ 76 ]. DOX promotes the activity of lncRNA KCNQ1OT1 by upregulating the expression of METL14, thereby inhibiting the activity of miR-7-5p, increasing the level of transferrin receptor, promoting iron absorption and the production of lipid reactive oxygen species, and inducing cardiomyocyte ferroptosis [ 77 ].…”