Abstract 15090: AMP-Activated Protein Kinase Upregulates Sodium-Dependent Glucose Transporter SGLT1, Which Contributes to Cardiac Ischemia-Reperfusion Injury
INTRODUCTION: AMP-activated protein kinase (AMPK) is cardioprotective during ischemia/reperfusion (I/R). We have identified a novel cardiac sodium glucose cotransporter, SGLT1, and determined that it is upregulated in transgenic mice with a mutation leading to AMPK hyperactivation. Therefore, we hypothesized that SGLT1 is a downstream target of AMPK and is involved in the cardiac response to I/R.
METHODS AND RESULTS: HL-1 cells treated in vitro with the AMPK activator AICAR (1mM) for 24 h had a 2.89±0.6 fold increase in SGLT1 mRNA (vs. vehicle, N=3, P<0.01), which was abrogated by the AMPK inhibitor compound C (10 μM). Simulated ischemia in HL-1 cells with NaCN (5 mM for 4 h) increased SGLT1 expression 3.6±1.3 fold (N=5, P<0.005), which was abrogated by compound C. SGLT1 RNAi in HL-1 cells improved cell survival following 4 h of ischemia from 52±2% to 86±3% (P<0.002). Transgenic mice with cardiomyocyte-specific knockdown of SGLT1 (TGSGLT1-DOWN) and wildtype (WT) littermates were subjected to ex vivo global ischemia for 20 min followed by reperfusion for 40 min. TGSGLT1-DOWN mice had improved post-ischemic peak systolic pressure vs. WT (67.6±3.0 vs. 44.6±2.5 mmHg, N=7, P<0.01). Post-ischemic dp/dt and -dp/dt were 1420±193.8 and -746.0 ±80.11 respectively in TGSGLT1-DOWN, both were significantly higher vs. WT (768.0±101.2 and -462.6±40.46 respectively, N=8, P<0.01). TGSGLT1-DOWN mice and WT littermates were subjected to in vivo regional I/R with 30 min of left anterior descending coronary artery ligation followed by 4 h of reperfusion. TGSGLT1-DOWN mice had a decreased ratio of infarct size to area at risk (AAR) vs. WT (0.03±0.01 vs. 0.14±0.03, N=3, P<0.05). TGSGLT1-DOWN mice exhibited decreased oxidative stress vs. WT (MDA 104±5 vs. 140±10 nmol/g tissue, N=4, P<0.05) and had decreased expression of the NOX2 subunit gp91 phox expression.
CONCLUSIONS: AMPK is an upstream regulator of cardiac SGLT1. Although AMPK generally mediates cardioprotection in I/R, transgenic knockdown of SGLT1 in mice improved post-I/R functional recovery, decreased infarction size, and decreased oxidative stress. These effects may be related to decreased oxidative stress. SGLT1 may be a novel therapeutic interventional target for ischemic heart disease.
- © 2013 by American Heart Association, Inc.