Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

Abstract

ObjectiveSodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.Methods and ResultsWe determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.ConclusionsCardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.

SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study

“…Further, if SGLT1 were inhibited by empagliflozin, myocardial function would be expected to decline, not improve. Consistent with this, SGLT1 inhibition by phlorizin (dual SGLT1/2 inhibitor) in experimental animals exerts a detrimental effect on LV function (35). We are unaware of any study that demonstrates that empagliflozin has a direct beneficial effect on the heart, unrelated to an effect on the SGLT2/SGLT1 transporters, although such an effect cannot be excluded.…”

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

“…The localization of SGLT1 in capillaries of the heart (and skeletal muscle), but not in capillaries of the small intestine had previously been reported by immunohistochemistry in rats [128]. More recently, Kashiwagi et al reported that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, including in cardiomyocytes, as assessed by immunostaining and immunoblotting with membrane fractionation [126]. Thus, cardiac SGLT1 could be involved in glucose transport from the capillaries into the cardiomyocytes.…”

“…However, the physiological role of SGLT1 in the heart remains elusive. Under basal conditions, the perfusion of phlorizin, a dual SGLT1/SGLT2 inhibitor, into the mouse heart did not change cardiac function as determined in the Langendorff model [126]. Banerjee and colleagues provided first evidence that the increase in cardiac glucose uptake induced by insulin and leptin in cultured mouse cardiomyocytes is inhibited by phlorizin, suggesting a potential role of SGLT1 in the hormone regulated glucose uptake in the mouse heart, but the in vivo relevance was not tested [125].…”

Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies

“…Since glucose is an essential substrate for myocardium particularly during ischemia, it is important to know the role of glucose transporters in the heart. A study has shown the presence of SGLT1 receptors on human as well as 'murine Langendorff perfused hearts' [28]. This study has also demonstrated that SGLT1 inhibitors may increase the risk of ischemia-reperfusion injury of the myocardium.…”

“…But the presence of SGLT2 on the myocardium and its interaction with SGLT1 still are fields for further experiment. More data will help us know the effects of SGLT2 on myocardial metabolism during normal state as well as during ischemic injury [28].…”