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.

高血糖在急性冠脉综合征 （ACS） 期间很常见，与糖尿病状态无关，预示着梗死面积过大和死亡率过高，但这种影响的潜在机制知之甚少。我们假设钠/葡萄糖相关转运蛋白 1 （SGLT1） 可能有助于 ACS 期间高葡萄糖的影响，并使用缺血再灌注损伤的离体啮齿动物心脏模型对此进行了检查。Langendorff 灌注大鼠心脏缺血 35 分钟，再灌注 2 小时，在 SGLT1 药物抑制剂存在下，再灌注期间给予可变葡萄糖和互惠甘露醇。通过 rtPCR、RNAscope 和免疫组化测定大鼠心肌 SGLT1 的表达，以及通过单细胞转录组学分析测定人心肌 SGLT1 的表达。非糖尿病大鼠心脏的高血糖加剧了再灌注损伤，在 11-22 mmol/L 葡萄糖下，梗死面积分别从 45 ± 3 增加到 65 ± 4% （p < 0.01），糖尿病心脏中没有关联 （32 ± 1-37 ± 5%，p = NS）。大鼠心脏在血管内皮和心肌细胞中表达 SGLT1 RNA 和蛋白，通过单核 RNA 测序在人心肌中也表达相似。大鼠 SGLT1 在糖尿病心脏与非糖尿病心脏中的表达显著降低 （0.608 ± 0.08 相比 1.116 ± 0.13 个探针/核，p < 0.01）。非糖尿病心脏中的药物抑制剂根皮苷、卡格列净或米格列净显示，阻断 SGLT1 而不是 SGLT2，消除了葡萄糖介导的过度再灌注损伤。 在再灌注过程中，葡萄糖升高对大鼠心脏有害，加剧非糖尿病心脏的心肌梗死，而糖尿病心脏对升高的葡萄糖有抵抗力，这一发现可能是由心肌 SGLT1 表达降低来解释的。SGLT1 在血管内皮细胞和心肌细胞中表达，抑制 SGLT1 可消除过量的葡萄糖介导的梗死。这些数据突出了 SGLT1 作为改善高血糖 ACS 患者发病率/死亡率结局的潜在临床转化靶点。