Objective: The aim of the present study was to explore potential contributions of histone demethylase KDM3A in the in vivo and in vitro MIRI and the underpinning mechanisms.
Methods and Results: Myocardial KDM3A expression was down-regulated under I/R injury. The global KDM3A-knocout rat, and KDM3A-overexpressed rats induced by in situ adenoviral transfection as a selective protocol due to the failure of transgenic rats generation, were utilized to investigate the effects of KDM3A in rat heart in response to I/R. The results showed that KDM3A knockout exaggerated cardiac dysfunction and necrosis, which were evidenced by reduced ejection fraction (EF) and fractional shortening (FS) as well as increased infarct size and necrotic marker enzymes. The deteriorated inflammation, mitochondria-dependent apoptosis and reactive oxygen species (ROS) were simultaneously indicated. Conversely, KDM3A overexpression developed ameliorated changes in I/R disorder. KDM3A overexpression also mitigated hypoxia/reoxygenation (H/R)-induced damages in isolated cardiomyocytes as characterized by enhanced cells viability and suppressed inflammation, apoptosis and ROS, whereas KDM3A knockdown using shRNA exerted opposite outcomes. Mechanistically, the I/R- and H/R-limited roles of KDM3A were associated with activating AKT-mediated pathways, and treatment with pharmacological inhibitor confirmed this speculation. ChIP-PCR assay further affirmed that KDM3A removed dimethylation of histone H3 lysine 9 (H3K9me2) on the promoter of AKT in cultured cardiomyocytes, which subsequently drove AKT expression and its downstream survival mediators.
Conclusion: These evidences suggest that KDM3A is available of alleviating multi-etiologies of MIRI at least in part via activation of AKT-modulated pathways.