Abstract 312: SGLT1 is Essential for Cardioprotection During Ischemia-Reperfusion Injury via Enhanced Glucose Utilization in Diet-induced Obese Mice

Abstract

Recent large clinical trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac SGLTs (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is a preferential substrate for myocardial metabolism during ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either non-selective SGLT-inhibitor phlorizin (to inhibit SGLT1) or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and dramatically increased infarct size (indicated by CPK release into perfusate and TTC staining) were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in both myocardial glucose uptake and cardiac tissue ATP content. In contrast, regardless of the diet condition, SGLT1 expression remained constant during IRI, whereas SGLT2 was not detected. Of note, phlorizin considerably reduced myocardial glucose uptake and decreased cardiac tissue ATP content after IRI, particularly in HFD. In conclusion, cardiac SGLT1 but not SGLT2 plays a compensatory protective role and contributes to cardiac energy metabolism during acute phase of IRI via enhanced glucose utilization, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.