Dexmedetomidine attenuates myocardial ischemia-reperfusion injury in vitro by inhibiting NLRP3 Inflammasome activation

Abstract

Background Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro. Methods We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined. Results Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1β, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1β and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. Conclusion Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

Neuroprotective Effect of Dexmedetomidine against Postoperative Cognitive Decline via NLRP3 Inflammasome Signaling Pathway

“…Similarly, we observed that YOH administration reversed the effect of Dex of the inflammatory response and cognitive impairment. Moreover, the administration of YOH with DEX increased the level of NLRP3 and ASC expression compared to the Dex only group, consistent with results obtained in previous studies [ 36 , 37 ]. Therefore, present study confirmed that the effects of Dex on the POCD condition are executed by directly regulating level of NLRP3 and ASC expression and activation.…”

Dexmedetomidine improves myocardial ischemia-reperfusion injury by increasing autophagy via PINK1/PRKN pathway

“…Increasing studies have proved that DEX has broad application prospects in the treatment of myocardial diseases in the future [24,25]. Previous research has suggested that DEX reduced MI/R injury by lessening oxidative stress, cardiomyocyte apoptosis, and inflammatory reactions [11,26,27]. Nev-ertheless, the mechanism at the molecular level of DEX's protection against MI/R injury requires more investigations.…”

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

“…Cells were treated with vehicle (saline), recombinant human IL-38 (10 ng/mL) or MCC950 (1 μM, 5479, Tocris Bioscience) ( 57 , 58 ) prior to an exposure to rh-matrilin-2 (2.0 μg/mL) for 72 h ( 19 ). Cell lysates were used for the assessment of ICAM-1, VCAM-1, RUNX2, and ALP proteins.…”