Regenerative Nanomedicine, Faculty of Pharmacy, UMR 1260, INSERM (French National Institute of Health and Medical Research), University of Strasbourg, 67000, Strasbourg, France.
Service de Cardiologie, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France.
Cardiovasc Diabetol. 2021 Mar 16;20(1):65. doi: 10.1186/s12933-021-01252-3.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular risk in type 2 diabetes patients independently of glycemic control. Although angiotensin II (Ang II) and blood-derived microparticles are major mediators of cardiovascular disease, their impact on SGLT1 and 2 expression and function in endothelial cells (ECs) and isolated arteries remains unclear.
ECs were isolated from porcine coronary arteries, and arterial segments from rats. The protein expression level was assessed by Western blot analysis and immunofluorescence staining, mRNA levels by RT-PCR, oxidative stress using dihydroethidium, nitric oxide using DAF-FM diacetate, senescence by senescence-associated beta-galactosidase activity, and platelet aggregation by aggregometer. Microparticles were collected from blood of patients with coronary artery disease (CAD-MPs).
Ang II up-regulated SGLT1 and 2 protein levels in ECs, and caused a sustained extracellular glucose- and Na-dependent pro-oxidant response that was inhibited by the NADPH oxidase inhibitor VAS-2780, the AT1R antagonist losartan, sotagliflozin (Sota, SGLT1 and SGLT2 inhibitor), and empagliflozin (Empa, SGLT2 inhibitor). Ang II increased senescence-associated beta-galactosidase activity and markers, VCAM-1, MCP-1, tissue factor, ACE, and AT1R, and down-regulated eNOS and NO formation, which were inhibited by Sota and Empa. Increased SGLT1 and SGLT2 protein levels were observed in the rat aortic arch, and Ang II- and eNOS inhibitor-treated thoracic aorta segments, and were associated with enhanced levels of oxidative stress and prevented by VAS-2780, losartan, Sota and Empa. CAD-MPs promoted increased levels of SGLT1, SGLT2 and VCAM-1, and decreased eNOS and NO formation in ECs, which were inhibited by VAS-2780, losartan, Sota and Empa.
Ang II up-regulates SGLT1 and 2 protein expression in ECs and arterial segments to promote sustained oxidative stress, senescence and dysfunction. Such a sequence contributes to CAD-MPs-induced endothelial dysfunction. Since AT1R/NADPH oxidase/SGLT1 and 2 pathways promote endothelial dysfunction, inhibition of SGLT1 and/or 2 appears as an attractive strategy to enhance the protective endothelial function.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可降低 2 型糖尿病患者的心血管风险，而不依赖于血糖控制。尽管血管紧张素 II（Ang II）和血液衍生的微粒是心血管疾病的主要介质，但它们对内皮细胞（ECs）和分离的动脉中 SGLT1 和 2 的表达和功能的影响仍不清楚。
从猪冠状动脉和大鼠动脉段中分离 ECs。通过 Western blot 分析和免疫荧光染色评估蛋白质表达水平，通过 RT-PCR 评估 mRNA 水平，通过二氢乙啶评估氧化应激，通过 DAF-FM 二乙酸酯评估一氧化氮，通过衰老相关的β-半乳糖苷酶活性评估衰老，通过血小板聚集仪评估血小板聚集。从患有冠状动脉疾病（CAD-MPs）的患者的血液中收集微粒。
Ang II 上调了 ECs 中的 SGLT1 和 2 蛋白水平，并引起了持续的细胞外葡萄糖和 Na 依赖性促氧化剂反应，该反应被 NADPH 氧化酶抑制剂 VAS-2780、AT1R 拮抗剂氯沙坦、索格列净（Sota，SGLT1 和 SGLT2 抑制剂）和恩格列净（Empa，SGLT2 抑制剂）抑制。Ang II 增加了衰老相关的β-半乳糖苷酶活性和标志物、VCAM-1、MCP-1、组织因子、ACE 和 AT1R，同时降低了 eNOS 和 NO 的形成，而 Sota 和 Empa 则抑制了这些作用。在大鼠主动脉弓和 Ang II 和 eNOS 抑制剂处理的胸主动脉段中观察到 SGLT1 和 SGLT2 蛋白水平增加，与氧化应激水平升高有关，并被 VAS-2780、氯沙坦、Sota 和 Empa 所抑制。CAD-MPs 促进了 ECs 中 SGLT1、SGLT2 和 VCAM-1 水平的升高，并降低了 eNOS 和 NO 的形成，而 VAS-2780、氯沙坦、Sota 和 Empa 则抑制了这些作用。
Ang II 在上皮细胞和动脉段中上调 SGLT1 和 2 蛋白表达，以促进持续的氧化应激、衰老和功能障碍。这种序列有助于 CAD-MPs 诱导的内皮功能障碍。由于 AT1R/NADPH 氧化酶/SGLT1 和 2 途径促进内皮功能障碍，因此抑制 SGLT1 和/或 2 似乎是增强保护性功能的有吸引力的策略。
