Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Abstract

Background: Recent 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 results: The 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. Conclusions: Cardiac 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.

Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure

“…Accordingly, in the present study we could not detect myocardial LV SGLT2 mRNA expression in controls or in those with end-stage HF. On the contrary, SGLT1 has been recently identified as a highly expressed, major glucose transporter in the heart alongside GLUT1 and GLUT4 [17][18][19][20][21]. In cases when upregulated, dual SGLT1/2 inhibitors and even SGLT2 inhibitors might modulate SGLT1 in the heart, but this is currently unclear [8].…”

“…In contrast, both healthy and diseased hearts express high levels of SGLT1 [17][18][19], which has been identified as a major glucose transporter in the myocardium besides the facilitative glucose transporters 1 and 4 (GLUT1 and 4) in humans and rodents [17][18][19][20][21][22][23]. The myocardial expression of SGLT1 in humans is altered in various cardiovascular disease states [16,18,24].…”

“…Despite its substantial clinical relevance, there is a gap of knowledge regarding the physiological and pathophysiological roles of SGLT1 in the myocardium [30]. Some studies in small animals suggested that pharmacological SGLT1/2 inhibition could exacerbate myocardial dysfunction following ischemia-reperfusion injury by inhibiting glucose uptake [19,21]. In cases when SGLT1 is upregulated in the heart, dual SGLT1/2 inhibitors or even SGLT2 inhibitors might affect myocardial SGLT1, but this is currently unclear [8].…”

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction

“…Fifthly, we did not assess whether empagliflozin therapy impacted MI size or area at risk ex vivo. However, Yoshi et al [23] demonstrated no impact on SGLT2i therapy upon myocardial injury using an ischemia reperfusion model, and we utilised a well validated echocardiographic technique to assess, and match infarct size prior to randomization [24], thus this is unlikely to account for the observed changes. Finally, we induced MI on young rats, with normal renal function unlike the older populations with comorbidities that account for the vast majority of patients affected by heart failure.…”

Major Influence of Diabetes on Hospitalization for Heart Failure in Patients With Ischemic Heart Diseases

“…9 Therefore, targeting the acceleration of myocardial glucose utilization may become of particular importance under insulin resistant conditions, such as DM, in which glucose utilization is impaired in response to various stimuli, including insulin stimulation as well as ischemic insult. 10 Together with insulin resistance as well as neurohumoral activation, such as enhanced catecholamine activity, the circulating free FA level and uptake into the myocardium are increased, exceeding the FA oxidation (FAO) capacity of the diabetic heart. The mismatch between FA uptake and FAO results in myocardial triglyceride accumulation, namely, lipotoxicity.…”