Key result
Hesperetin pre-treatment reduces infarct size and improves cardiac function in I/R-injured mice via PPARα activation.
Why the study?
Myocardial ischemia/reperfusion injury is a common complication of restoring blood flow in acute myocardial infarction, but no effective therapies directly reduce this injury.
Does hesperetin pre-treatment reduce myocardial ischemia/reperfusion injury in a mouse model?
Does hesperetin pre-treatment reduce myocardial ischemia/reperfusion injury in a mouse model?
Hesperetin protects against myocardial ischemia/reperfusion injury by upregulating CISD2 via the PPARα pathway in a mouse model.
Hesperetin may protect against myocardial I/R injury in mice; hypothesis-generating and leaves clinical translation open.
Background Myocardial ischemia/reperfusion (I/R) injury is a common and unavoidable complication of restoring blood flow in acute myocardial infarction (AMI), yet no effective therapies currently exist to directly reduce this injury. Purpose This study aimed to investigate the role of CISD2, a key regulator of cellular homeostasis and mitochondrial function, in myocardial I/R injury and explore potential therapeutic strategies to protect the heart. Methods To assess the role of CISD2 in myocardial I/R injury, we employed wild-type, cardiac-specific CISD2 knockout, and CISD2 transgenic mice in a model of myocardial I/R injury induced by ligation of the left anterior descending artery. To translate these genetic findings into a potential therapeutic strategy, we tested hesperetin, a natural flavonoid known to enhance CISD2 expression. Results CISD2 expression was significantly reduced following I/R, and lower CISD2 levels were associated with greater myocardial injury and worse outcomes. Conversely, elevated CISD2 expression conferred a dose-dependent reduction in mortality after AMI, underscoring its protective role in cardiac tissue. Pre-treatment with hesperetin restored myocardial CISD2 levels, reduced infarct size, and improved cardiac function in I/R-injured mice. Mechanistically, hesperetin activated the PPARα pathway, leading to CISD2 upregulation, which preserved mitochondrial integrity, maintained cellular metabolism, and reduced ROS production, demonstrating that hesperetin’s cardioprotective effects are at least partly mediated through a PPARα-CISD2-dependent pathway. Conclusions Elevating CISD2 expression preserves cellular metabolism and protects against myocardial I/R injury, establishing CISD2 as a key regulator of cardiac resilience under I/R stress. These findings highlight CISD2 enhancement, potentially via the PPARα-activated hesperetin pathway, as a promising therapeutic strategy to reduce I/R injury in patients with AMI.
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Yeh et al. (2025) studied Myocardial ischemia/reperfusion injury. Hesperetin was evaluated on Infarct size, cardiac function, and mortality. Pre-treatment with hesperetin reduced infarct size and improved cardiac function in I/R-injured mice by activating the PPARα pathway to upregulate CISD2.
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