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


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.

SUBMITTER: Li Z 

PROVIDER: S-EPMC6704393 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Li Zhao Z   Agrawal Vineet V   Ramratnam Mohun M   Sharma Ravi K RK   D'Auria Stephen S   Sincoular Abigail A   Jakubiak Margurite M   Music Meredith L ML   Kutschke William J WJ   Huang Xueyin N XN   Gifford Lindsey L   Ahmad Ferhaan F  

Cardiovascular research 20190901 11


<h4>Aims</h4>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.<h4>Methods and results</h4>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 reperfu  ...[more]

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