Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?

Nikolaou, Panagiota; Mylonas, Nikolaos; Makridakis, Manousos; Makrecka-Kūka, Marina; Iliou, Aikaterini; Zerikiotis, Stelios; Efentakis, Panagiotis; Kampoukos, Stavros; Kostomitsopoulos, Nikolaos; Vilšķe̅rsts, Reinis; Ikonomidis, Ignatios; Lambadiari, Vaia; Zuurbier, Coert J.; Latosinska, Agnieszka; Vlahou, Antonia; Dimitriadis, George; Iliodromitis, Efstathios K.; Andreadou, Ioanna

doi:10.1007/s00395-022-00934-7

Cited by 37 publications

(28 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For in vivo experiments, DAPA was purchased from commercially available dapagliflozin tablets (Forxiga Tab 10 mg, AstraZeneca AB, United States). DAPA was diluted with sterile water for injection (WFI) and given to animals by intragastric administration, as previously shown ( Nikolaou et al, 2022 ). Primary antibodies against β-tubulin (1:5,000, Cat.…”

Section: Methodsmentioning

confidence: 99%

“…Cardiomyocytes and cardiac tissues lack SGLT2 expression, and the cardioprotective effects of SGLT2 inhibitors should be mediated by other targets and signaling pathways. Hence, discussions of the mechanism of SGLT2i have shown that it can inhibit myocardial inflammation ( Lin K. et al, 2022 ), reduce oxidative stress ( Nikolaou et al, 2021 ), regulate autophagy ( Yu et al, 2021 ), improve mitochondrial function, and reduce myocardial cell apoptosis ( Nikolaou et al, 2022 ). However, the MIRI-improving effects of DAPA by inhibiting cardiomyocyte ferroptosis have not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Meanwhile, a very recent CHIEF-HF remote, patient-centered randomized trial confirmed the cardioprotective effect of canagliflozin in patients without diabetes [40]. Additionally, the beneficial effects of SGLT2 inhibitors on cardio-endpoints observed in clinical trials have been confirmed in animal studies [41]. SGLT2 inhibitors may also have SGLT2 independent effects in vitro [42,43].…”

Section: Discussionmentioning

confidence: 94%

Canagliflozin Pretreatment Attenuates Myocardial Dysfunction and Improves Postcardiac Arrest Outcomes After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Abbott

et al. 2023

Cardiovasc Drugs Ther

View full text Add to dashboard Cite

Objective The SGLT2 inhibitor, canagliflozin, not only reduces glycemia in patients with type 2 diabetes but also exerts cardioprotective effects in individuals without diabetes. However, its potential beneficial effects in cardiac arrest have not been characterized. The purpose of this study was to examine the protective effect of canagliflozin pretreatment on postresuscitation-induced cardiac dysfunction in vivo. Methods Male C57/BL6 mice were randomized to vehicle (sham and control) or canagliflozin treatment groups. All mice except for the sham-operated mice were subjected to potassium chloride-induced cardiac arrest followed by chest compressions and intravenous epinephrine for resuscitation. Canagliflozin therapy efficacies were evaluated by electrocardiogram, echocardiography, histological analysis, inflammatory response, serum markers of myocardial injury, protein phosphorylation analysis, and immunohistological assessment. Results Canagliflozin-pretreated mice exhibited a higher survival rate (P < 0.05), a shorter return of spontaneous circulation (ROSC) time (P < 0.01) and a higher neurological score (P < 0.01 or P < 0.001) than control mice after resuscitation. Canagliflozin was effective at improving cardiac arrest and resuscitation-associated cardiac dysfunction, indicated by increased left ventricular ejection fraction and fractional shortening (P < 0.001). Canagliflozin reduced serum levels of LDH, CK-MB and α-HBDH, ameliorated systemic inflammatory response, and diminished the incidence of early resuscitation-induced arrhythmia. Notably, canagliflozin promoted phosphorylation of cardiac STAT-3 postresuscitation. Furthermore, pharmacological inhibition of STAT-3 by Ag490 blunted STAT-3 phosphorylation and abolished the cardioprotective actions of canagliflozin. Conclusions Canagliflozin offered a strong cardioprotective effect against cardiac arrest and resuscitation-induced cardiac dysfunction. This canagliflozin-induced cardioprotection is mediated by the STAT-3-dependent cell-survival signaling pathway.

show abstract

“…The usage of DEX (S3075), YOH (S2373), and Stattic (S7024) from Selleck was adapted from previous reports. 17,18 In vitro (Figure 1B), neonatal rat cardiomyocytes were randomly assigned to the following 5 groups: (1) control: cells were incubated with vehicle of Stattic for 8 hours and then saline for 1 hour before normoxic culture for 9 hours. (2) H6R3: cells were incubated with vehicle for 8 hours and then saline for 1 hour before 6 hours of hypoxia and 3 hours of reoxygenation.…”

Section: Experimental Designmentioning

confidence: 99%

Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

Zhaorong

Hong

Wen

et al. 2023

Anesthesia &Amp; Analgesia

View full text Add to dashboard Cite

BACKGROUND: Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood. METHODS: In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 μg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment. RESULTS: In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response (P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis (P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 μM DEX pretreatment improved cell viability (P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis (P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic. CONCLUSIONS: DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro.

show abstract

Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?

Cited by 37 publications

References 101 publications

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

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

Canagliflozin Pretreatment Attenuates Myocardial Dysfunction and Improves Postcardiac Arrest Outcomes After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

Contact Info

Product

Resources

About