Sodium–Glucose CoTransporter-2 Inhibitor Empagliflozin Ameliorates Sunitinib-Induced Cardiac Dysfunction via Regulation of AMPK–mTOR Signaling Pathway–Mediated Autophagy

Abstract

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have been shown to decrease the adverse cardiac events and risks of cardiovascular mortality among patients with or without diabetes, which has made these drugs promising treatment options for patients with chronic heart failure. Cardiac dysfunction is a common and severe side effect induced by cancer chemotherapies, which seriously affects the prognosis and life quality of tumor patients. However, it is not clear whether SGLT2 inhibitors have cardiovascular benefits in patients with cancer chemotherapy–related cardiac dysfunction. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role against sunitinib (SNT)-induced cardiac dysfunction in a mouse model.Methods: Male C57BL/6J mice were randomized into control (control, n = 8), empagliflozin (EMPA, n = 8), sunitinib (SNT, n = 12), or sunitinib and empagliflozin coadministration (SNT + EMPA, n = 12) groups. EMPA, SNT, or SNT-combined EMPA was given via oral gavage for consecutive 28 days. Cardiovascular functions and pathological changes were examined, and the underlying mechanisms of EMPA’s effects were investigated in H9c2 cardiomyocytes.Results: Mice in the SNT group exhibited dramatically elevated blood pressure (systolic blood pressure [SBP] 134.30 ± 6.455 mmHg vs. 114.85 ± 6.30 mmHg) and impaired left ventricular function (left ventricular ejection fraction [LVEF] 50.24 ± 3.06% vs. 84.92 ± 2.02%), as compared with those of the control group. However, EMPA could ameliorate SNT-induced cardiotoxicity, both in terms of SBP (117.51 ± 5.28 mmHg vs. 134.30 ± 6.455 mmHg) and LVEF (76.18 ± 5.16% vs. 50.24 ± 3.06 %). In H9c2 cardiomyocytes, SNT-induced cardiomyocyte death and cell viability loss as well as dysfunction of adenosine 5’-monophosphate–activated protein kinase–mammalian target of rapamycin (AMPK-mTOR) signaling–mediated autophagy were restored by EMPA. However, these favorable effects mediated by EMPA were blocked by the inhibition of AMPK or autophagy.Conclusion: EMPA could ameliorate SNT-induced cardiac dysfunction via regulating cardiomyocyte autophagy, which was mediated by the AMPK-mTOR signaling pathway. These findings supported that SGLT2 inhibitor therapy could be a potential cardioprotective approach for cardiovascular complications among patients receiving SNT. However, these favorable effects still need to be validated in clinical trials.

Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis

“…6 d). To further confirm effects of si-TFAF6 on LPS plus ATP-induced changes in autophagy, BV2 cells were transfected with mCherry-GFP-LC3 adenovirus to observe autophagic flow as reported [ 28 ]. Results showed that LPS plus ATP stimulation triggered a dramatic decrease in autophagosomes (yellow puncta) and autolysosomes (red puncta) in BV2 cells, and si-TRAF6 transfection reversed the result with more autolysosomes (Fig.…”

“…We used mCherry green fluorescent protein (GFP)-tagged LC3 adenovirus (AdmCherry-GFP-LC3) (Hanbio, China) to observe the change in autophagy as previously reported [ 28 ]. Green fluorescence will be quenched when GFP enters the acidic environment in lysosomal.…”

Cardiorenal protection of SGLT2 inhibitors—Perspectives from metabolic reprogramming

“… 76 In a series of experimental studies, SGLT2 inhibitors were reported to inhibit the mTOR signalling pathway and thereby maintain redox homeostasis, upregulate autophagy, and suppress inflammation, which may partially explain the cardiorenal protective mechanisms induced by SGLT2 inhibition. 76 , 117 , 118 , 119 , 120 , 121 …”

Sodium–Glucose Cotransporter 2 Inhibitors Work as a “Regulator” of Autophagic Activity in Overnutrition Diseases

“…Several pathways are reported in improving the myocardial cell’s autophagy deficiency of diabetes, such as the activation of AMPK ( Aragon-Herrera et al, 2019 ) and through the microRNA-30d/KLF9/VEGFA pathway ( Zhang et al, 2020 ). SGLT2 inhibitors are also reported to suppress mTORC1 formation ( Ren et al, 2021 ) and activate SIRT1 ( Packer, 2020b ) and HIF-2α ( Packer, 2020a ) of myocardial cells, which could contribute to the improvement of autophagy.…”