Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition

Abstract

Reperfusion is essential for ischemic myocardium but paradoxically leads to myocardial damage that worsens cardiac functions. Ferroptosis often occurs in cardiomyocytes during ischemia/reperfusion (I/R). The SGLT2 inhibitor dapagliflozin (DAPA) exerts cardioprotective effects independent of hypoglycemia. Here, we investigated the effect and potential mechanism of DAPA against myocardial ischemia/reperfusion injury (MIRI)-related ferroptosis using the MIRI rat model and hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocytes. Our results show that DAPA significantly ameliorated myocardial injury, reperfusion arrhythmia, and cardiac function, as evidenced by alleviated ST-segment elevation, ameliorated cardiac injury biomarkers including cTnT and BNP and pathological features, prevented H/R-triggered cell viability loss in vitro. In vitro and in vivo experiments showed that DAPA inhibited ferroptosis by upregulating the SLC7A11/GPX4 axis and FTH and inhibiting ACSL4. DAPA notably mitigated oxidative stress, lipid peroxidation, ferrous iron overload, and reduced ferroptosis. Subsequently, network pharmacology and bioinformatics analysis suggested that the MAPK signaling pathway was a potential target of DAPA and a common mechanism of MIRI and ferroptosis. DAPA treatment significantly reduced MAPK phosphorylation in vitro and in vivo, suggesting that DAPA might protect against MIRI by reducing ferroptosis through the MAPK signaling pathway.

Dapagliflozin alleviates high-fat-induced obesity cardiomyopathy by inhibiting ferroptosis

“…A study by Jhuo et al examined myocardial mitochondrial function in HFDinduced metabolic disorders and obesity, and the authors found that empagli ozin-treated mice exhibited improved cardiomyocyte mitochondrial biogenesis function [40]. In a study on SGLT2is and ischemiareperfusion injury, Dapa was demonstrated to improve myocardial injury and cardiac function in rats by inhibiting ferroptosis by inhibiting ACSL4 and upregulating the SLC7A11/GPX4 axis and FTH [41].…”

Trimetazidine Attenuates Ischemia/Reperfusion-Induced Myocardial Ferroptosis by Modulating the Sirt3/Nrf2-GSH System and Reducing Mitochondrial Oxidative Stress

“…H9C2 was starved with glucose-free DMEM involving 2% FBS for 4 hours before each anoxia. As mentioned earlier, the experimental procedure of anoxia/reoxygenation (A/R) was conducted on H9C2 in order to replicate the conditions of myocardial ischemia-reperfusion [34]. Brie y, cardiomyocytes were transferred to DMEM without glucose and serum and cultivated in an anoxic incubator (containing 1%O 2 , 4% CO 2 and 95% N 2 , Heracell™ VIOS™ CO 2 Incubator, United States) at 37°C for 2 h. Following this, the glucose-free and serum-free medium was substituted with a conventional medium and placed in the standard incubator for a duration of 4 hours to replicate the e cacy of ischemia-reperfusion injury.…”

“…As was already said, the MI/R injury model was established and exploited [34]. SD male rats in good health were chosen, given 50 mg/kg of sodium pentobarbital to make them sleepy, and then laid down on surgery plates and held in place with leather straps.…”

WTAP-mediated m6A modification of lncRNA Snhg1 improves myocardial ischemia-reperfusion injury via miR-361-5p/OPA1-dependent mitochondrial fusion

“…Myocardial infarction is the most popular primary symptom of IHD [ 3 ]. In clinical therapy, prompt reperfusion is crucial to decrease infarct size, save the ischemic myocardium, and prevent the onset of heart failure [ 1 , 4 ]. Nevertheless, reperfusion may induce myocardial injury named myocardial ischemia/reperfusion injury (MIRI) [ 4 – 6 ].…”

“…In clinical therapy, prompt reperfusion is crucial to decrease infarct size, save the ischemic myocardium, and prevent the onset of heart failure [ 1 , 4 ]. Nevertheless, reperfusion may induce myocardial injury named myocardial ischemia/reperfusion injury (MIRI) [ 4 – 6 ]. Increasing evidence reveals that reperfusion injury accounts for 50% of the approximate myocardial infarct size [ 7 , 8 ].…”