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KDM3A Attenuates Myocardial Ischemic and Reperfusion Injury by Ameliorating Cardiac Microvascular Endothelial Cell
Bofang Zhang1, Gen Liu1, Bing Huang1
1Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430000, China.
Abstract:
Cardiac microvascular endothelial cell ischemia-reperfusion (CMEC I/R) injury occurs in approximately 50% of acute myocardial infarction patients subjected to successful revascularization therapy. This injury leads to cardiac microcirculatory system dysfunctions, which seriously affect cardiac functions and long-term prognostic outcomes. Previously, we elucidated the role of lysine-specific demethylase 3A (KDM3A) in protecting cardiomyocytes from I/R injury; however, its roles in CMEC I/R injuries have yet to be fully established. In this study, hypoxia/reoxygenation (H/R) treatment significantly impaired CMEC functions and induced their pyroptosis, accompanied by KDM3A downregulation. Then, gain- and loss-of-function assays were performed to investigate the roles of KDM3A in CMEC H/R injury in vitro. KDM3A knockout enhanced CMEC malfunctions and accelerated the expressions of pyroptosis-associated proteins, such as NLRP3, cleaved-caspase-1, ASC, IL-1β, GSDMD-N, and IL-18. Conversely, KDM3A overexpression developed ameliorated alternations in CMEC H/R injury. In vivo, KDM3A knockout resulted in the deterioration of cardiac functions and decreased the no-reflow area as well as capillary density. Mechanistically, KDM3A activated the PI3K/Akt signaling pathway and ameliorated I/R-mediated CMEC pyroptosis. In conclusion, KDM3A is a promising treatment target for alleviating CMEC I/R injury.
Insights
Lysine-specific demethylase 3A (KDM3A) protects cardiac microvascular endothelial cells (CMECs) from injury. KDM3A downregulation exacerbates CMEC pyroptosis and cardiac dysfunction after ischemia-reperfusion, highlighting KDM3A as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Biochemistry
Background:
- Cardiac microvascular endothelial cell (CMEC) ischemia-reperfusion (I/R) injury impacts 50% of acute myocardial infarction patients undergoing revascularization.
- This injury impairs cardiac function and long-term outcomes by disrupting the cardiac microcirculation.
- While KDM3A's role in cardiomyocyte protection is known, its function in CMEC I/R injury remains unclear.
Purpose of the Study:
- To investigate the role of lysine-specific demethylase 3A (KDM3A) in cardiac microvascular endothelial cell (CMEC) ischemia-reperfusion (I/R) injury.
- To elucidate the underlying mechanisms of KDM3A's involvement in CMEC pyroptosis and dysfunction.
Main Methods:
- Hypoxia/reoxygenation (H/R) treatment was used to induce CMEC injury in vitro.
- Gain- and loss-of-function assays (KDM3A knockout and overexpression) were performed.
- In vivo studies assessed cardiac function, no-reflow area, and capillary density following KDM3A manipulation.
Main Results:
- H/R treatment downregulated KDM3A, impaired CMEC function, and induced pyroptosis.
- KDM3A knockout exacerbated CMEC pyroptosis and cardiac dysfunction, while KDM3A overexpression ameliorated injury.
- KDM3A activation of the PI3K/Akt pathway was identified as a key mechanism in reducing I/R-mediated CMEC pyroptosis.
Conclusions:
- KDM3A plays a protective role against cardiac microvascular endothelial cell (CMEC) ischemia-reperfusion (I/R) injury.
- KDM3A downregulation contributes to CMEC pyroptosis and subsequent cardiac dysfunction.
- KDM3A represents a potential therapeutic target for mitigating CMEC I/R injury and improving cardiac outcomes.
