Abstract
Abstract 18818: Sodium Glucose Co-Transporter 1 (SGLT1) is a Novel Contributor to Cardiac Ischemia/Reperfusion (I/R) Injury Through PKC- and ERK-Dependent Mechanisms
Circulation (New York, N.Y.), Vol.134(Suppl_1 Suppl 1), pp.A18818-A18818
11/11/2016
Abstract
IntroductionWe have shown that AMP-activated protein kinase (AMPK) upregulates SGLT1, which contributes to cardiac ischemia/reperfusion (I/R) injury by activating NADPH oxidase 2 (Nox2). AMPK is known to interact with MAPK/ERK pathway. Studies in non-cardiac cells have suggested that SGLT1 stabilizes EGFR, which in turns activates PKC. PKC leads to phosphorylation of p47 phox, a regulatory subunit of Nox2.HypothesisERK mediates upregulation of SGLT1 by AMPK, and EGFR mediates activation of Nox2 by SGLT1 in cardiac I/R injury.Methods and ResultsEx vivo studiesWe constructed two transgenic mouse models(1) cardiomyocyte-specific knockdown of SGLT1 (TG), using transgenic RNAi technology; and (2) cardiomyocyte-specific doxycycline-suppressible conditional overexpression of SGLT1 (TG). Isolated perfused hearts from TG mice, TG mice, and wildtype (WT) littermates were subjected to 20 min global no-flow ischemia followed by 20 min reperfusion. Compared to WT hearts, TG and TG hearts respectively showed less and greater impairment of cardiac contractility following I/R (peak left ventricular systolic pressure [LVSP]WT, 77±9; TG, 130 ±17; TG, 63±10 mmHg; P<0.05). Phosphorylation of PKC and p47 phox was decreased in TG hearts following I/R. Compared to WT hearts, TG hearts exhibited greater PKC activation (0.380±0.047 vs 0.650±0.028 arbitrary units, P<0.05). Compared to WT hearts, PKC α and β expression was decreased in TG hearts and increased in TG hearts, but PKC ε expression was increased in TG hearts and decreased in TG hearts. Co-immunoprecipitation showed interactions between SGLT1 and EGFR, and between EGFR and PKC, but not between SGLT1 and PKC. In vitro studiesCultured HL-1 cells were treated with vehicle, metformin (AMPK activator), U0126 (ERK inhibitor) or metformin+U0126 for 18h. Metformin treatment increased AMPK phosphorylation and SGLT1 expression, an effect that was abrogated by U0126.ConclusionsAMPK upregulates SGLT1 through the MAPK/ERK pathway. PKC α and β may be downstream effectors of SGLT1 in cardiac I/R injury. EGFR may mediate activation of PKC α and β by SGLT1.
Details
- Title: Subtitle
- Abstract 18818: Sodium Glucose Co-Transporter 1 (SGLT1) is a Novel Contributor to Cardiac Ischemia/Reperfusion (I/R) Injury Through PKC- and ERK-Dependent Mechanisms
- Creators
- Zhao Li - University of IowaLindsey GiffordFerhaan Ahmad
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.134(Suppl_1 Suppl 1), pp.A18818-A18818
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/11/2016
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984302193802771
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