The histone demthylase KDM3A protects the myocardium from ischemia/reperfusion injury via promotion of ETS1 expression

Abstract

Our prior studies have characterized the participation of histone demethylase KDM3A in diabetic vascular remodeling, while its roles in myocardial ischemia/reperfusion (I/R) injury (MIRI) remain to be illustrated. Here we show that KDM3A was significantly downregulated in rat I/R and cellular hypoxia/reoxygenation (H/R) models. Subsequently, gain- and loss-of-function experiments were performed to investigate the effects of KDM3A in the settings of MIRI. KDM3A knockout exacerbated cardiac dysfunction and cardiomyocytes injury both in vivo and in vitro. The deteriorated mitochondrial apoptosis, reactive oxygen species, and inflammation were simultaneously observed. Conversely, KDM3A overexpression developed the ameliorated alternations in MIRI. Mechanistically, the MIRI-alleviating effects of KDM3A were associated with the enhancement of ETS1 expression. ChIP-PCR affirmed that KDM3A bound to the ETS1 promoter and removed dimethylation of histone H3 lysine 9 (H3K9me2), thus promoting ETS1 transcription. Our findings suggest that KDM3A is available for alleviating multi-etiologies of MIRI through the regulation of ETS1.

KDM3A Attenuates Myocardial Ischemic and Reperfusion Injury by Ameliorating Cardiac Microvascular Endothelial Cell Pyroptosis

“…Therefore, KDM3A is pivotal in the regulatory network of cardiovascular diseases. In our latest study, KDM3A protected the myocardium from I/R injury and regulated inflammatory reactions as well as death of cardiomyocytes [26]. Nevertheless, the potential significance of KDM3A in CMEC I/R injury has not been conclusively established.…”

“…Hypoxia/Reoxygenation Models In Vitro. Isolation of CMECs from wild-type (WT) and KDM3A global knockout rats (male, 20 days old) with SD backgrounds was done using the enzyme dissociation method as previously reported [26]. CMECs were cultured in an endothelial cell culture medium, and at a confluence of 80-90%, cells were subjected to anoxic and reoxygenation treatments.…”

“…Establishment of KDM3A Knockout Rats. The KDM3A global knockout rats were generated using the CRISPR/ Cas9 gene-editing technology as previously described [26,30]. We designed and created one single guide RNA (sgRNA) flanked exon 5 of the KDM3A gene in rats.…”

“…of Myocardial Infarct Sizes. The myocardial I/R model was established as reported [26]. Rats (male, 6-8 weeks, 220-250 g) were anaesthetized via intraperitoneal administration of pentobarbital sodium (40 mg/kg) (Sigma-Aldrich, USA), and a left parasternal incision was performed.…”

“…Lysine-specific demethylase 3A (KDM3A), which is also referred to as Jumonji domain-containing 1A (JMJD1A), is a member of the Jumonji c domain-containing protein family that functions as a histone demethylase to specifically demethylate the dimethylated histone H3 lysine 9 (H3K9me2) [25]. H3K9 methylation is deemed as a transcriptionally repressive mark; upregulation of KDM3A levels may inhibit H3K9me2 demethylation and activate the transcription of its specific target genes [26]. It has been reported that KDM3A has a role in various biological processes, such as cell proliferation, migration, tumor cell infiltration, and angiogenesis [27,28].…”