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Targeting Inhibition of Histone Lysine Demethylase Kdm5b Ameliorates Myocardial Ischemia-Reperfusion Injury by Restoring Brinp2 Expression [RNA-seq]

ABSTRACT: Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge lacking effective therapies, largely due to incomplete mechanistic understanding. While reactive oxygen species (ROS) overproduction is a central pathogenic event, direct antioxidant strategies have largely failed clinically. Epigenetic regulation, particularly histone methylation, has emerged as a critical player in cardiac stress responses, yet the role of specific histone demethylases in I/R remains largely unexplored. Here, we identify lysine-specific demethylase 5B (Kdm5b), an eraser of the active transcription mark H3K4me3, as a key pathogenic mediator and therapeutic target in myocardial I/R injury. Kdm5b is markedly upregulated in hypoxic cardiomyocytes, leading to reduced H3K4me3 levels. Pharmacological inhibition of Kdm5b with AS8351, or genetic knockdown, protects cardiomyocytes from hypoxia/reoxygenation-induced (H/R) cell death, oxidative stress, and mitochondrial dysfunction. In mice, post-reperfusion AS8351 administration improves cardiac function and reduces infarct size. Integrative transcriptomic and epigenomic analyses identify Brinp2 as a direct transcriptional target of Kdm5b. Kdm5b occupies the Brinp2 locus, and its inhibition restores H3K4me3 occupancy and Brinp2 expression. Notably, Brinp2 knockdown largely abolishes AS8351-mediated protection both in vitro and in vivo. Collectively, our findings reveal a previously unrecognized Kdm5b-H3K4me3- Brinp2 epigenetic axis governing cardiomyocyte survival during I/R stress and position Kdm5b as a promising therapeutic target for ischemic heart disease.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE329213 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Coronary heart disease is the leading cause of death worldwide. After an acute myocardial infarction, early reperfusion reduces infarct size, which correlates with improved clinical outcomes. Paradoxically, reperfusion although relieving ischemia, accelerates apoptosis in injured cardiomyocytes, which has led to the view that myocardial salvage is futile beyond the first few hours of reperfusion. In murine hearts subjected to 90 min of coronary artery occlusion and then 48 h of reperfusion, we show transient activation of intrinsic prosurvival insulin-like growth factor-1 (IGF-1) signaling. In these hearts, acute IGF-1 receptor inhibition decreases the abundance of prosurvival signaling molecules, and markedly activates caspase-3, a potent effector of apoptosis, in infarct border zone cardiomyocytes. We found that mouse mast cell protease-4 (MMCP-4) degraded IGF-1 in vitro by a novel catalytic activity of chymases. In vivo, this degradation, which is triggered by mast cell infiltration into the peri-infarct region and MMCP-4 extravasation, between 48 and 72 h post-ischemia/reperfusion (I/R), attenuates IGF-1 prosurvival signaling. In MMCP-4-deficient mice, while infarct size is not reduced at 24 h post-I/R, at 72 h post-I/R myocardial IGF-1 levels and signaling are increased, resulting in activation of the survival kinases Akt and ERK, inhibition of caspase-3, and reduced myocardial cell death. As a consequence, I/R-mediated loss of viable myocardium, adverse cardiac remodeling and contractile impairment are markedly reduced. Cardiomyocyte survival with consequent myocardial salvage may thus be possible even days after an ischemic insult, making them a novel therapeutic target for delayed cardioprotective therapy. Group 1 is wild type C57Bl6 uninjured hearts. These mice were not undergone any surgery and used as controls. Group 2 are wild type C57Bl6 72 h post-ischemia reperfusion (IR) injury hearts. These mice for subjected to ischemia reperfusion (IR) involving 90 min of left anterior descending coronary artery occlusion followed by reperfusion for 3 days or 72 h.

Project description:Aims A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischemia / reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stress in vivo. Methods and results Transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodeling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure-volume loop analysis. Histological indices of remodeling, including cardiomyocyte cross-sectional diameter, capillary density and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 minutes of ischemia followed by 24 hours of reperfusion, AKIP1-TG mice displayed a significant 2-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signaling molecules NF-κB, protein kinase A or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP-synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium induced swelling, indicative of reduced MPT pore formation. Conclusions In contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodeling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acute myocardial infarction.

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Targeting Inhibition of Histone Lysine Demethylase Kdm5b Ameliorates Myocardial Ischemia-Reperfusion Injury by Restoring Brinp2 Expression [RNA-seq]

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