Dexmedetomidine preconditioning attenuates ferroptosis in myocardial ischemia-reperfusion injury via α2 adrenergic receptor activation

Abstract

Objective: Dexmedetomidine (Dex) is a potent agonist of the α2 adrenergic receptor that has been shown to possess sedative and hypnotic properties. Dex can protect against myocardial ischemia-reperfusion injury (MIRI) by inhibiting ferroptosis. However, these studies were based on Dex post-conditioning, and the role of α2 adrenergic receptors in this process is unclear. In this study, we investigated whether Dex preconditioning can prevent MIRI by attenuating ferroptosis and whether this effect depends on α2 adrenergic receptors in rats.

Methods: Male Sprague-Dawley rats were randomly assigned to five groups: sham (saline-treated), I/R (ischemia-exposed), Dex + I/R (Dex pre-treatment), Dex + Yoh + I/R (Dex and yohimbine pre-treatment), and Yoh + I/R (yohimbine pre-treatment). Cardiac function, myocardial infarction, and morphological changes were assessed. Transmission electron microscopy was used to analyze mitochondrial morphology. Ferroptosis-related indicators and lipid peroxidation were measured using western blotting and qRT-PCR.

Results: Our findings indicated that Dex preconditioning improved cardiac function, reduced infarct size and apoptosis, and inhibited ferroptosis in the rat myocardium after MIRI. These effects were associated with the upregulation of Nrf2, SLC7A11, and GPX4 expression, as well as the downregulation of Ferritin, TFR1, ACSL4, COX2, IL-1β, IL-6, and TNF-α expression. Importantly, yohimbine, an α2 adrenergic receptor antagonist, abolished these protective effects.

Conclusion: These results suggest that Dex preconditioning can prevent MIRI by attenuating ferroptosis via α2 adrenergic receptor activation and by modulating the Nrf2/SLC7A11/GPX4 pathway.

Keywords: Dexmedetomidine; Ferroptosis; Myocardial ischemia-reperfusion injury; SLC7A11; α2 adrenergic receptor.

Fig. 1

Dex preconditioning reduced myocardial infarct size and improved cardiac function. (A) Cardiac function was measured with echocardiography. (B) Left ventricular ejection fraction (LVEF). (C) Left ventricular fractional shortening (LVFS). (D) Myocardial infarction was detected by TTC staining. (E) Infarct size ratio. (F) CK-MB level examined by ELISA. n = 3–6/group. All data are presented as the mean ± SEM. ∗P < 0.05 vs. the Sham group. ^#P < 0.05 vs. the I/R group. ^&P < 0.05 vs. the Dex + I/R group.

Fig. 2

Dex preconditioning improved the morphology and myocardial ultrastructure. (A) Cardiac pathological injury was detected by HE staining ( × 100). (B) Ultrastructural changes of the myocardium and mitochondria were observed using transmission electron microscopy. (C) Ratio of intact to total mitochondria (%). n = 3/group. ∗P < 0.05 vs. the Sham group. ^#P < 0.05 vs. the I/R group. ^&P < 0.05 vs. the Dex + I/R group.

Fig. 3

Dex preconditioning altered ferroptosis-related indicators. (A) SOD activity. (B) MDA level. (C) GSH level. (D) GSSG level. (E) The ratio of GSH to GSSG. (F) Iron level. n = 3/group. All data are presented as the mean ± SEM. ∗P < 0.05 vs. the Sham group. ^#P < 0.05 vs. the I/R group. ^&P < 0.05 vs. the Dex + I/R group.

Fig. 4

Dex preconditioning mitigated MIRI by modulating ferroptosis-related proteins and mRNA. (A) Ferritin protein level. (B) TFR1 protein level. (C) ACSL4 protein level. (D) GPX4 protein level. (E) SLC7A11 protein level. (F) SLC7A11 mRNA expression. n = 3/group. All data are presented as the mean ± SEM. ∗P < 0.05 vs. the Sham group. ^#P < 0.05 vs. the I/R group. ^&P < 0.05 vs. the Dex + I/R group.

Fig. 5

Dex preconditioning enhanced antioxidant activity and reduced inflammation in rat myocardial tissues. (A) Nrf2 protein level. (B) COX2 protein level. (C) IL-1β mRNA expression. (D) IL-6 mRNA expression. (E) TNF-α mRNA expression. n = 3/group. All data are presented as the mean ± SEM. ∗P < 0.05 vs. the Sham group. ^#P < 0.05 vs. the I/R group. ^&P < 0.05 vs. the Dex + I/R group.