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

• Published in: Cardiovascular research Vol. 115; no. 11; pp. 1646 - 1658
• Main Authors: Li, Zhao, Agrawal, Vineet, Ramratnam, Mohun, Sharma, Ravi K, D'Auria, Stephen, Sincoular, Abigail, Jakubiak, Margurite, Music, Meredith L, Kutschke, William J, Huang, Xueyin N, Gifford, Lindsey, Ahmad, Ferhaan
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2019
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Cell Line; Disease Models, Animal; Editor's Choice; 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; Original; Oxidative Stress; Protein Kinase C - metabolism; Signal Transduction; Sodium-Glucose Transporter 1 - deficiency; Sodium-Glucose Transporter 1 - genetics; Sodium-Glucose Transporter 1 - metabolism; PKC; Reactive oxygen species; SGLT1; Cardiac ischaemia/reperfusion; Nox2
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvz037

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.