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Sodium-Glucose Co-transporter-2 Inhibitor of Dapagliflozin Attenuates Myocardial Ischemia/Reperfusion Injury by Limiting NLRP3 Inflammasome Activation and Modulating Autophagy.

ABSTRACT: Background: The sodium-glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin improves cardiovascular outcomes in patients with type 2 diabetes in a manner that is partially independent of its hypoglycemic effect. These observations suggest that it may exert a cardioprotective effect by another mechanism. This study explored the effects of dapagliflozin on myocardial ischemia/reperfusion injury in a mouse model. Materials and Methods: For the in vivo I/R studies, mice received 40 mg/kg/d dapagliflozin, starting 7 days before I/R. Evans Blue/TTC double-staining was used to determine the infarct size. Serum levels of cTnI, CK-MB, and LDH were measured. Inflammation, autophagy protein expression, and caspase-1 activity changes were measured at the protein level. Primary cardiomyocytes were used to investigate the direct effect of dapagliflozin on cardiomyocytes and to verify whether they have the same effect as observed in in vivo experiments. Result: A high dose of dapagliflozin significantly reduced infarct size and decreased the serum levels of cTnI, CK-MB, and LDH. Dapagliflozin also reduced serum levels of IL-1β, reduced expression of myocardial inflammation-related proteins, and inhibited cardiac caspase-1 activity. The treatment restored autophagy flux and promoted the degradation of autophagosomes. Relief of inflammation relied on autophagosome phagocytosis of NLRP3 and autophagosome clearance after lysosome improvement. 10 μM dapagliflozin reduced intracellular Ca²⁺ and Na⁺ in primary cardiomyocytes, and increasing NHE1 and NCX expression mitigated dapagliflozin effects on autophagy. Conclusion: Dapagliflozin protects against myocardial ischemia/reperfusion injury independently of its hypoglycemic effect. High-dose dapagliflozin pretreatment might limit NLRP3 inflammasome activation and mediate its selective autophagy. Dapagliflozin directly acts on cardiomyocytes through NHE1/NCX.

SUBMITTER: Yu YW

PROVIDER: S-EPMC8785320 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Cytoprotection by activated protein C (aPC) after ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation, and hence, cell-death forms disjunct from immunologically silent apoptosis are, in theory, more likely to be relevant. Because pyroptosis (ie, cell death resulting from inflammasome activation) is typically observed in IRI, we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRIs. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutation abolished the protective effect of aPC, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via proteinase-activated receptor 1 (PAR-1) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Accordingly, inhibiting PAR-1 signaling, but not the anticoagulant properties of aPC, abolished the ability of aPC to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficiently as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression after IRI was corroborated in renal IRI, where the tissue protective effect of aPC was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1-dependent inflammasome activation and that mimicking biased aPC PAR-1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.

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Sodium-Glucose Co-transporter-2 Inhibitor of Dapagliflozin Attenuates Myocardial Ischemia/Reperfusion Injury by Limiting NLRP3 Inflammasome Activation and Modulating Autophagy.

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