Abstract
BackgroundRecent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (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 an important preferential substrate for myocardial energy metabolism under conditions of ischemia–reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes.Methods and resultsThe hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin 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 the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size 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 myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD.ConclusionsCardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.
Highlights
Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients
After 30-min global ischemia followed by 40-min reperfusion, high-fat diet (HFD) per se significantly reduced left ventricular developed pressure (LVDP) recovery (22.5% ± 3.5% versus 68.3% ± 7.1% recovery from baseline, P < 0.01, Fig. 2c, d) and the rate pressure product (RPP), calculated as LVDP × heart rate, in order to consider the impact of the heart rate on the cardiac function
In the present study using diet-induced obesity model, we showed that the inhibition of cardiac SGLT1 by phlorizin during the acute phase of ischemia–reperfusion injury (IRI) led to an impaired cardiac functional recovery and increased myocardial injury, which were associated with significant reductions in the myocardial glucose uptake enhanced by IRI
Summary
Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. Targeting the acceleration of myocardial glucose utilization during the acute phase of IRI is a potential therapeutic strategy for protecting cardiomyocyte and improving the cardiac functional recovery [2, 5, 7, 8]. This approach may become of particular importance under insulinresistant conditions, such as diabetes mellitus, in which the glucose utilization is further impaired in response to various stimuli, including insulin stimulation as well as ischemic insult. It was reported that the cardiac GLUT4 expression is decreased under insulin-resistant conditions, such as diabetes, in association with the reduction in glucose uptake, leading to impaired glucose utilization in the heart [10, 13, 14]
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