Abstract
ObjectiveThe purpose of the present study was to evaluate the role of co-treatment of rosuvastatin (RSV) and dapagliflozin (DGZ) preconditioning in myocardium ischemia/reperfusion (I/R) injury and to further investigate the underlying mechanism.MethodsSprague-Dawley (SD) rats (n = 25) were divided into five groups randomly: (1) Sham, (2) I/R, (3) I/R + RSV (10 mg/kg), (4) IR + DGZ (1 mg/kg), and (5) I/R + RSV (10 mg/kg) + DGZ (1 mg/kg). The I/R model was induced with 30 min of left anterior descending occlusion followed by 120 min of reperfusion.Results In vivo pretreatment with RSV and DGZ, respectively, showed a significant reduction of infarction size, a significant increase in the levels of left ventricular systolic pressure, and maximal rate increase in left ventricular pressure (+dp/dt max), decrease in the levels of left ventricular end-diastolic pressure (LVEDP), maximal rate of decrease of left ventricular pressure (−dp/dt max) and activity of cardiac enzymes of creatine kinase (CK), creatine kinase MB isoenzymes (CK-MB), and hyper-tensive cardiac troponin I compared with the I/R group. H9C2 cells were exposed to hypoxia/reoxygenation to simulate an I/R model. In vitro administration of 25 µM RSV and 50 µM DGZ significantly enhanced cell viability, upregulated the expression levels of p-PI3K, p-Akt, p-mTOR, and Bcl-2, whereas it downregulated cleaved-caspase3, Bax. TUNEL assay indicated that pretreatment with RSV and DGZ decreased the apoptosis of H9C2 cells.ConclusionThe combination of RSV and DGZ significantly enhances the cardioprotective effects compared with RSV or DGZ alone. RSV and DGZ have the potential cardioprotective effects against I/R injury by activating the PI3K/AKt/mTOR signaling pathway.
Highlights
It has been reported that acute myocardial infarction contributes to high rates of morbidity and mortality in the past few decades in China [1]
Numerous studies have confirmed that apoptosis was stimulated to reduce the myocardium cell survival via phosphatidylinositol-3kinase (PI3K)/protein kinase B (AKt)/mechanistic target of the rapamycin signaling pathway in the acute myocardial I/R injury [6,7]
This study aimed to investigate whether the preconditioning with the combination of RSV and DGZ is superior to the RSV or DGZ alone in the treatment of cardiac I/R injury, and if so, whether the PI3K/AKt/mechanistic target of the rapamycin (mTOR) signaling pathway still plays a key role in it
Summary
It has been reported that acute myocardial infarction contributes to high rates of morbidity and mortality in the past few decades in China [1]. In recent 20 years, the prompt myocardial revascularization can recover the myocardium blood flow and reduce ischemiainduced injury [2]. It may inevitably cause contractile dysfunction, severe arrhythmias, extremely to death, the complicated pathophysiological process of which was referred to as myocardial ischemia/reperfusion (I/R) injury [3]. Apoptosis is a complex regulated pathological process in the programed cell death, playing a vital role during the myocardial I/R injury. Numerous studies have confirmed that apoptosis was stimulated to reduce the myocardium cell survival via phosphatidylinositol-3kinase (PI3K)/protein kinase B (AKt)/mechanistic target of the rapamycin (mTOR) signaling pathway in the acute myocardial I/R injury [6,7]. In clinical practice, it is of great importance and necessity to explore and resolve the intricate I/R-associated phenomenon
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