Abstract 15175: Critical Role of Sodium-Glucose Cotransporter 1 in the Cardioprotection Through the Maintenance of Energy Production During Ischemia-Reperfusion Injury

Abstract

Glucose becomes an important preferential substrate for cardiac metabolism and ATP generation under specific pathological conditions, such as ischemia. Glucose utilization is initiated by glucose uptake, which is mainly controlled by glucose transporters. Although the role of passive glucose transporters (GLUTs) has been investigated intensively, little is known about the functional significance of the other active transporter, sodium-glucose cotransporter 1 (SGLT1), in the heart. We herein hypothesized that cardiac SGLT1 plays a critical role for cardioprotection during ischemia-reperfusion injury (IRI), possibly through the enhanced glucose utilization for the energy production. To test this, we studied the effects of 10-4 M of phlorizin, SGLT1 inhibitor, on the baseline function and its response to global ischemia (20 minutes)-reperfusion (40 minutes) injury in mouse Langendorff perfusion model, where SGLT1, but not SGLT2, is highly expressed, as confirmed by immunoblotting assay. Although phlorizin did not affect baseline function, its administration during IRI significantly impaired recovery in left ventricular contraction (% recovery of baseline; 67.3±4.5 vs. 89.7±6.8%, n=5 each, P<0.05) and rate pressure product (18600±1290 vs. 25100±1010 mmHg•bpm, n=5 each, P<0.01), associated with increased infarct size demonstrated by TTC staining as well as CPK activity released into the perfusate (20.8±9.5 vs. 2.0±0.6 U•g, n≥3, P<0.05). Of note, the onset of ischemic contracture, which is thought to be initiated by ATP depletion in cardiomyocytes, was earlier with phlorizin perfusion (288±21 vs. 364±27 sec, n≥8, P<0.05). Consistent with this, the significant reduction of tissue ATP content was observed in phlorizin perfused heart (4.81±0.61 vs. 6.87±0.13 μmol/g tissue, n≥4, P<0.05). In conclusion, these data demonstrate that SGLT1 represents an important cardioprotective mechanism against IRI possibly through the maintenance of ATP generation. Our findings shed new light on the essential role of SGLT1 for the optimization of cardiac energy metabolism by the enhanced glucose availability during ischemia, thus leading to substantial myocardial protection after severe ischemic insults.