Saudi Cultural Missions Theses & Dissertations
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Item Restricted Investigating Sodium-Glucose Co-Transporter 1 (SGLT1) in Myocardium and Its Role in High Glucose Ischemia-Reperfusion Injury(2023-04-28) Almalki, Alhanoof; Bell, RobertBackground: Hyperglycaemia is a common finding in both diabetic and non-diabetic patients presenting with acute coronary syndrome (ACS); it is a strong predictor of prognosis and is associated with an increase in the mortality rate. Interestingly, non- diabetic patients with hyperglycaemia have a worse prognosis than diabetic patients with the same serum glucose concentration. However, the role of hyperglycaemia in ischemia- reperfusion injury is still not fully understood. Clinical outcome trials with sodium-glucose co-transporter-2 (SGLT2) inhibitors demonstrate a significant improvement in cardiovascular outcomes, yet the mechanism is not fully understood especially given that SGLT2 is not expressed in the heart. In contrast, sodium glucose co-transporter-1 (SGLT1) is detected in the heart, but it is currently unknown whether SGLT1 plays a role in infarct augmentation prior to and/or after reperfusion and whether it has a cardioprotective function. Aims: 1) characterise the expression of SGLT1 in the myocardium, (2) determine the role of high glucose during ischemia-reperfusion injury, (3) investigate whether SGLT1 is involved in a glucotoxicity injury during IRI, and (4) whether inhibiting SGLT1 with an SGLT inhibitor may reduce infarct size. Method: SGLT1 mRNA expression in rat myocardium was determined using Reverse transcription polymerase chain reaction (RT-PCR) and in-situ hybridization (RNAScope). Ex-vivo Langendorff ischemia-reperfusion perfusion model was used to examine the effect of high glucose [22mmol] on the myocardium during reperfusion in comparison to standard glucose [11mmol]. Canagliflozin, a mixed SGLT1 and SGLT2 inhibitor (1moL/L to block the SGLT2 and SGLT1 and 5nmol/L to block the SGLT2 only), and mizagliflozin, a novel SGLT1 inhibitor (100nmol/L), were administered after ischemia-reperfusion injury, infarct size was measured using triphenyl tetrazolium chloride (TTC) staining. Results: we found that SGLT1 mRNA is expressed in the whole myocardium. SGLT1 mRNA expression is significantly suppressed by 50% in diabetic heart compared to non-diabetic heart, with no evidence of compensatory expression of myocardial SGLT2. We found that commercially available SGLT1 antibodies were unreliable and not adequate for ascertaining protein expression. We confirmed that high glucose [22mM] at reperfusion exacerbates infarct size by over 40%, and inhibiting SGLT1 with canagliflozinon, at a dose that would block SGLT2 and SGLT1, and mizagliflozin completely abrogates the glucose- induced exacerbation of myocardial infarction. Conclusion: Glucose-mediated exacerbation of infarction is via SGLT1, and this exacerbation can be abrogated by SGLT1 inhibition. SGLT1 expression is downregulated in diabetic states, hence the smaller infarcts in our model, and potentially explains lower mortality rate in diabetic ACS patients. SGLT1 represents a novel approach for clinical translation for ACS patients presenting with hyperglycaemia.6 0