Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pole of Pharmacology and Therapeutics, Brussels, Belgium.
Sci Rep. 2017 Jan 27;7:41166. doi: 10.1038/srep41166.
Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to HG. In contrast, myo-inositol (transported through SMIT1) reproduced the toxic effects of HG. SMIT1 overexpression exacerbated glucotoxicity and sensitized cardiomyocytes to HG, whereas its deletion prevented HG-induced NOX2 activation. In conclusion, our results show that heart SMIT1 senses HG and triggers NOX2 activation. This could participate in the redox signaling in hyperglycemic heart and contribute to the pathophysiology of diabetic cardiomyopathy.
高血糖（HG）通过激活 NADPH 氧化酶 2（NOX2）刺激心脏中活性氧的产生。这种产生不依赖于葡萄糖代谢，但需要钠/葡萄糖协同转运蛋白（SGLT）。已知有 7 种 SGLT 同工型（SGLT1 至 6 和钠-肌醇协同转运蛋白-1，SMIT1），尽管它们在心脏中的表达和功能仍不清楚。我们研究了这 7 种同工型，发现只有 SGLT1 和 SMIT1 在小鼠、大鼠和人心肌中表达。在心肌细胞中，半乳糖（通过 SGLT1 转运）不会激活 NOX2。因此，SGLT1 缺乏并不能防止 HG 诱导的 NOX2 激活，这排除了它在细胞对 HG 反应中的作用。相比之下，肌醇（通过 SMIT1 转运）再现了 HG 的毒性作用。SMIT1 的过表达加剧了葡萄糖毒性作用，并使心肌细胞对 HG 敏感，而其缺失则阻止了 HG 诱导的 NOX2 激活。总之，我们的研究结果表明，心脏 SMIT1 感知 HG 并触发 NOX2 激活。这可能参与了高血糖心脏中的氧化还原信号转导，并有助于糖尿病心肌病的病理生理学。
