Key result
Macrophage GLUD1 activation preserves cardiac function and limits ischemia-reperfusion injury by regulating mitochondrial ROS.
Why the study?
Excessive free radical production and dysregulated immune responses contribute to myocardial ischemia-reperfusion (IR) injury, but the mechanisms by which macrophages regulate reactive oxygen species homeostasis and orchestrate immune responses during IR injury remain elusive.
Does systemic activation of GLUD1 or adoptive transfer of monocytes pre-treated with a GLUD1 activator mitigate myocardial ischemia-reperfusion injury and preserve cardiac function in mice subjected to IR injury?
Does systemic activation of GLUD1 or adoptive transfer of monocytes pre-treated with a GLUD1 activator mitigate myocardial ischemia-reperfusion injury and preserve cardiac function in mice subjected to IR injury?
Macrophage GLUD1 acts as a critical regulator of mitochondrial redox balance and immune homeostasis during myocardial ischemia-reperfusion injury, representing a potential therapeutic target to preserve cardiac function.
Macrophage metabolic shifts in IR injury merit mechanistic follow-up; leaves open therapeutic targeting in AMI pending validation.
Excessive free radical production and dysregulated immune responses contribute to myocardial ischemia‐reperfusion (IR) injury. However, the mechanisms by which macrophages regulate reactive oxygen species (ROS) homeostasis and orchestrate immune responses during IR injury remain elusive. Here, we show that glutamate dehydrogenase 1 (GLUD1) expression is induced in monocytes from patients with acute myocardial infarction after interventional therapy and in cardiac‐recruited macrophages from mice subjected to IR injury. GLUD1‐deficient macrophages exacerbate IR injury by increasing mitochondrial ROS accumulation and amplifying pro‐inflammatory responses. Mechanistically, GLUD1 deficiency leads to mitochondrial ROS accumulation due to reduced NADPH/NADP + and GSH/GSSG ratios during IR injury. Elevated mitochondrial ROS inhibits PHD2 activity, stabilizing HIF‐1α and enhancing NF‐κB signaling, promoting the release of pro‐inflammatory factors and exacerbating myocardial damage. Systemic activation of GLUD1 or adoptive transfer of monocytes pre‐treated with a GLUD1 activator preserved cardiac function and mitigated IR injury. These findings highlight macrophage GLUD1 as a critical regulator of redox balance and immune homeostasis, presenting a promising therapeutic target for alleviating IR injury and preserving cardiac function.
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Jin et al. (2026) studied Myocardial ischemia-reperfusion injury and acute myocardial infarction. GLUD1 activation or adoptive transfer of GLUD1 activator-treated monocytes vs. GLUD1 deficiency / control was evaluated on Cardiac function and myocardial ischemia-reperfusion injury. Macrophage GLUD1 activation and adoptive transfer of GLUD1-activated monocytes preserved cardiac function and mitigated myocardial ischemia-reperfusion injury by regulating mitochondrial ROS.
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