2. Academic Validation
  3. SGLT1 contributes to glucose-mediated exacerbation of ischemia-reperfusion injury in ex vivo rat heart

SGLT1 contributes to glucose-mediated exacerbation of ischemia-reperfusion injury in ex vivo rat heart

  • Basic Res Cardiol. 2024 Aug 1. doi: 10.1007/s00395-024-01071-z.
Alhanoof Almalki # 1,  Sapna Arjun # 1,  Idris Harding 1,  Hussain Jasem 1,  Maria Kolatsi-Joannou 2,  Daniyal J Jafree 2 3 4,  Gideon Pomeranz 2 3,  David A Long 2 3,  Derek M Yellon 1,  Robert M Bell 5
Affiliations

Affiliations

  • 1 Hatter Cardiovascular Institute, Institute for Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
  • 2 Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
  • 3 UCL Centre for Kidney and Bladder Health, London, UK.
  • 4 UCL MB/PhD Programme, Faculty of Medical Sciences, University College London, London, UK.
  • 5 Hatter Cardiovascular Institute, Institute for Cardiovascular Science, University College London, 67 Chenies Mews, London, WC1E 6HX, UK. Rob.bell@ucl.ac.uk.
  • # Contributed equally.
PMID: 39088085 DOI: 10.1007/s00395-024-01071-z
Abstract

Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.

Keywords

Diabetes; Hyperglycemia; Myocardial infarction; Reperfusion injury; SGLT1; SGLT2.

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