Abstract
BackgroundMyocardial 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.MethodsWe 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.ResultsDexmedetomidine 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.ConclusionDexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.
Highlights
Acute myocardial infarction (AMI) represents a leading cause of death in patients with coronary heart disease [1]
The NLRP3 protein is expressed in Cardiac fibroblast (CF) rather than CMs To verify the localization of NLRP3, the expression of NLRP3 in cocultures of CFs and CMs was determined by laser scanning confocal microscopy
The results showed that H/R increased the levels of TNF-α and IL-18 in the CF supernatant (Fig. 5a, b) and the levels of IL-1β in CF lysates (Fig. 5e,), which were dramatically decreased in the D, 950, and D + 950 groups
Summary
Acute myocardial infarction (AMI) represents a leading cause of death in patients with coronary heart disease [1]. Experimental studies in AMI animal models suggest that lethal reperfusion injury accounts for up to 50% of the final size of the myocardial infarct [3]. Several studies have indicated that the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in MIRI [6]. NLRP3 inflammasomes include NLRP3, apoptosis-related dot-like protein containing a CARD (ASC) and Caspase-1. The formation and activation of NLRP3 inflammasome promotes further myocardial injury after cardiac ischemia reperfusion [7]. 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. We investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro
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