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- Title
Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia/reperfusion injury.
- 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
- Abstract
Aims 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. Methods and results 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. Conclusion 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.
- Subjects
PROTEIN kinase C; EPIDERMAL growth factor receptors; REPERFUSION injury; NADPH oxidase; SODIUM-glucose cotransporters; ISCHEMIA; HEART cells
- Publication
Cardiovascular Research, 2019, Vol 115, Issue 11, p1646
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvz037