Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression

Abstract

Jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, specifically catalyzes the demethylation of H3K27 (H3K27me3) and regulates gene expression. Sestrin2 (SESN2), a stress-inducible protein, protected against doxorubicin (DOX)-induced cardiomyopathy by regulating mitophagy and mitochondrial function. Here, the expression of JMJD3 was increased and that of SESN2 was decreased in both the heart samples from patients with dilated cardiomyopathy and chronic DOXstimulation induced cardiomyopathy. Inhibition or knockdown of JMJD3 attenuated DOX-induced cardiomyocytes apoptosis, mitochondrial injury and cardiac dysfunction. However, JMJD3 overexpression aggravated DOX-induced cardiomyopathy, which were relieved by SESN2 overexpression. JMJD3 inhibited the transcription of SESN2 by reducing tri-methylation of H3K27 in the promoter region of SESN2. In conclusion, JMJD3 negatively regulated SESN2 via decreasing H3K27me3 enrichment in the promoter region of SESN2, subsequently inducing mitochondrial dysfunction and cardiomyocytes apoptosis. Targeting the JMJD3-SESN2 signaling axis may be a potential therapeutic strategy to protect against DOX-mediated cardiomyopathy.

JMJD5 attenuates oxygen–glucose deprivation and reperfusion‐induced injury in cardiomyocytes through regulation of HIF‐1α‐BNIP3

“…14 For example, JMJD3 reduced H3K27me3 in the promoter region of sestrin2, and knockdown of JMJD3 ameliorated doxorubicin-induced cardiomyopathy. 15 JMJD3 also demethylated H3K27me3 at the promoter of β-MHC, and inhibition of JMJD3 attenuated isoproterenol-induced cardiac hypertrophy through suppression of β-MHC. 16 Therefore, lysine methylation of histones regulated by JMJDs was associated with cardiovascular diseases.…”

Epigallocatechin-3-gallate pretreatment alleviates doxorubicin-induced ferroptosis and cardiotoxicity by upregulating AMPKα2 and activating adaptive autophagy

“…Studies have confirmed that Dox is transformed into highly oxidative metabolites in mitochondria and induces redox imequilibrium [ 52 ]. There are many reports that mitochondrial mediated DIC causes apoptosis, and mitochondria have also become crucial targets for possible intervention [ [73] , [74] , [75] , [76] ]. Our previous studies have found that some phytochemicals upregulated 14-3-3γ expression, phosphorylated Bad, promoted the migration of Bcl-2 to mitochondria, reduced mPTP openness, inhibited apoptosis of cardiomyocytes and vascular endothelial cells, and resisted Dox toxic injury [ [12] , [13] , [14] , [15] ].…”

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

“…Histone modification affects many cellular pathways essential for the normal function and development of the heart and blood vessels (110,(118)(119)(120). The methyltransferase SET7 induces the upregulation of NF-κB p65 as a result of enhanced monomethylation of H3K4 in aortic ECs (121).…”