Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia/reperfusion injury

Zhao Li; Vineet Agrawal; Mohun Ramratnam; Ravi K Sharma; Stephen D'Auria; Abigail Sincoular; Margurite Jakubiak; Meredith L Music; William J Kutschke; Xueyin N Huang; Lindsey Gifford; Ferhaan Ahmad

doi:10.1093/cvr/cvz037

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Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia/reperfusion injury

Journal article

Open access

Peer reviewed

Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia/reperfusion injury

Zhao Li, Vineet Agrawal, Mohun Ramratnam, Ravi K Sharma, Stephen D'Auria, Abigail Sincoular, Margurite Jakubiak, Meredith L Music, William J Kutschke, Xueyin N Huang, …

Cardiovascular research, Vol.115(11), pp.1646-1658

09/01/2019

DOI: 10.1093/cvr/cvz037

PMCID: PMC6704393

PMID: 30715251

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Abstract

We previously reported that sodium-dependent glucose cotransporter 1 (SGLT1) is highly expressed in cardiomyocytes and is further up-regulated in ischaemia. This study aimed to determine the mechanisms by which SGLT1 contributes to ischaemia/reperfusion (I/R) injury. Mice with cardiomyocyte-specific knockdown of SGLT1 (TGSGLT1-DOWN) and wild-type controls were studied. In vivo, the left anterior descending coronary artery was ligated for 30 min and reperfused for 48 h. Ex vivo, isolated perfused hearts were exposed to 20 min no-flow and up to 2 h reperfusion. In vitro, HL-1 cells and isolated adult murine ventricular cardiomyocytes were exposed to 1 h hypoxia and 24 h reoxygenation (H/R). We found that TGSGLT1-DOWN hearts were protected from I/R injury in vivo and ex vivo, with decreased infarct size, necrosis, dysfunction, and oxidative stress. 5'-AMP-activated protein kinase (AMPK) activation increased SGLT1 expression, which was abolished by extracellular signal-related kinase (ERK) inhibition. Co-immunoprecipitation studies showed that ERK, but not AMPK, interacts directly with SGLT1. AMPK activation increased binding of the hepatocyte nuclear factor 1 and specificity protein 1 transcription factors to the SGLT1 gene, and HuR to SGLT1 mRNA. In cells, up-regulation of SGLT1 during H/R was abrogated by AMPK inhibition. Co-immunoprecipitation studies showed that SGLT1 interacts with epidermal growth factor receptor (EGFR), and EGFR interacts with protein kinase C (PKC). SGLT1 overexpression activated PKC and NADPH oxidase 2 (Nox2), which was attenuated by PKC inhibition, EGFR inhibition, and/or disruption of the interaction between EGFR and SGLT1. During ischaemia, AMPK up-regulates SGLT1 through ERK, and SGLT1 interacts with EGFR, which in turn increases PKC and Nox2 activity and oxidative stress. SGLT1 may represent a novel therapeutic target for mitigating I/R injury.

AMP-Activated Protein Kinases - metabolism

Animals

Cell Line

Disease Models, Animal

ELAV-Like Protein 1 - metabolism

ErbB Receptors - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Female

Hepatocyte Nuclear Factor 1 - metabolism

Male

Mice, Knockout

Myocardial Infarction - genetics

Myocardial Infarction - metabolism

Myocardial Infarction - pathology

Myocardial Infarction - physiopathology

Myocardial Reperfusion Injury - genetics

Myocardial Reperfusion Injury - metabolism

Myocardial Reperfusion Injury - pathology

Myocardial Reperfusion Injury - physiopathology

Myocytes, Cardiac - metabolism

Myocytes, Cardiac - pathology

NADPH Oxidase 2 - metabolism

NADPH Oxidases - metabolism

Necrosis

Oxidative Stress

Protein Kinase C - metabolism

Signal Transduction

Sodium-Glucose Transporter 1 - deficiency

Sodium-Glucose Transporter 1 - genetics

Sodium-Glucose Transporter 1 - metabolism

Details

Title: Subtitle: Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia/reperfusion injury
Creators: Zhao Li - University of Iowa
Vineet Agrawal - University of Pittsburgh
Mohun Ramratnam - William S. Middleton Memorial Veterans Hospital
Ravi K Sharma - University of Pittsburgh
Stephen D'Auria - University of Pittsburgh
Abigail Sincoular - Roy J. and Lucille A. Carver College of Medicine
Margurite Jakubiak - Roy J. and Lucille A. Carver College of Medicine
Meredith L Music - University of Iowa
William J Kutschke - University of Iowa
Xueyin N Huang - University of Pittsburgh
Lindsey Gifford - University of Iowa
Ferhaan Ahmad - University of Iowa
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.115(11), pp.1646-1658
DOI: 10.1093/cvr/cvz037
PMID: 30715251
PMCID: PMC6704393
NLM abbreviation: Cardiovasc Res
ISSN: 0008-6363
eISSN: 1755-3245
Grant note: R01 HL135000 / NHLBI NIH HHS U01 HL108642 / NHLBI NIH HHS 16POST27770035 / American Heart Association-American Stroke Association
Language: English
Date published: 09/01/2019
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984297510502771

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