Abstract 102: Cardiac Sodium/Glucose Cotransporter 1, a Novel Cardiac Glucose Transporter, Is Cardioprotective in Ischemia-Reperfusion Injury
Background: The expression of cardiac sodium/glucose cotransporter 1 (SGLT1) is up-regulated in ischemic heart disease. However, the regulation and the biological role of SGLT1 activity in cardiomyocytes are unclear.
Hypothesis: We hypothesize that SGLT1 inhibition during ischemia-reperfusion (IR) will lead to worsening cardiac function and recovery. In addition we hypothesize that SGLT1 expression is upregulated by increased AMPK activity in ischemia.
Methods: Transgenic mice with cardiac-specific RNAi knockdown of SGLT1 (TGSGLT1-KD) were subjected to ex vivo IR (n > 3/group) using a Langendorff hanging heart preparation with 15 min of no-flow ischemia and 20 min of reperfusion while undergoing hemodynamic monitoring. FVB strain wild-type 8-12 week-old male mice (n > 3/group) were administered either the SGLT1 inhibitor phlorizin (400 mg/kg IP) or vehicle and subjected to in vivo ischemia for 30 min by ligation of the left anterior descending (LAD) coronary artery. Hearts were harvested 48 hours later. In vitro studies were conducted in HL-1 cardiomyocytes subjected to 1 h of simulated ischemia with 1 mM NaCN. HL-1 cells were also treated with 1 mM AICAR, an AMPK activator, for 16 hours and SGLT1 expression was measured.
Results: In ex vivo IR studies, there was an impairment in the early recovery of double product in the TGSGLT1-KD mice compared to control mice (37% vs 92% at 1 min into reperfusion, P< 0.05). In in vivo IR studies, phlorizin led to a marked increase in oxidative stress documented by cardiac malondialdehyde (MDA) (control 1.00±0.00; IR 1.55±0.35; IR + phlorizin 16.15±0.40, P<0.001),an increase in apoptosis documented by TUNEL staining, and hemodynamic impairment: +dP/dt (mmHg/sec), control 11445±504, IR 9811±2613, IR + phlorizin 5139±481, P<0.05; -dP/dt (mmHg/sec), control -10625±589, IR -6770±1142, IR + phlorizin -4153±474, P<0.05. In HL-1 cardiomyocytes, there was a 6.7-fold increase in SGLT1 expression after simulated ischemia, and a 2.0-fold increase after AICAR exposure.
Conclusion: SGLT1 expression increases when cardiomyocytes are subjected to ischemia, an effect that may be mediated by AMPK. Inhibition of SGLT1 leads to impaired myocardial recovery from ischemia.
- © 2012 by American Heart Association, Inc.