Institute of Immunology and Department of Cardiology at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, China.
Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, and Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Hangzhou, China.
Cell Mol Life Sci. 2024 Nov 9;81(1):448. doi: 10.1007/s00018-024-05486-8.
Vascular calcification is a complication that is frequently encountered in patients affected by atherosclerosis, diabetes, and chronic kidney disease (CKD), and that is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). At present, there remains a pressing lack of any effective therapies that can treat this condition. The sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) has shown beneficial effects in cardiovascular disease. The role of this inhibitor in the context of vascular calcification, however, remains largely uncharacterized. Our findings revealed that DAPA treatment was sufficient to alleviate in vitro and in vivo osteogenic transdifferentiation and vascular calcification. Interestingly, our study demonstrated that DAPA exerts its anti-calcification effects on VSMCs by directly targeting SGLT2, with the overexpression of SGLT2 being sufficient to attenuate these beneficial effects. DAPA was also able to limit the glucose levels and NAD/NADH ratio in calcified VSMCs, upregulating sirtuin 1 (SIRT1) in a caloric restriction (CR)-dependent manner. The SIRT1-specific siRNA and the SIRT1 inhibitor EX527 attenuated the anti-calcification effects of DAPA treatment. DAPA was also to drive SIRT1-mediated deacetylation and consequent degradation of hypoxia-inducible factor-1α (HIF-1α). The use of cobalt chloride and proteasome inhibitor MG132 to preserve HIF-1α stability mitigated the anti-calcification activity of DAPA. These analyses revealed that the DAPA/SGLT2/SIRT1 axis may therefore represent a viable novel approach to treating vascular calcification, offering new insights into how SGLT2 inhibitors may help prevent and treat vascular calcification.
血管钙化是动脉粥样硬化、糖尿病和慢性肾脏病（CKD）患者经常遇到的并发症，其特征是血管平滑肌细胞（VSMC）的成骨转分化。目前，仍然迫切需要任何有效的治疗方法来治疗这种情况。钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂达格列净（DAPA）已显示出对心血管疾病的有益作用。然而，这种抑制剂在血管钙化中的作用在很大程度上仍未得到描述。我们的研究结果表明，DAPA 治疗足以缓解体外和体内成骨转分化和血管钙化。有趣的是，我们的研究表明，DAPA 通过直接靶向 SGLT2 发挥其抗钙化作用，SGLT2 的过表达足以减弱这些有益作用。DAPA 还能够限制钙化 VSMC 中的葡萄糖水平和 NAD/NADH 比值，以依赖于热量限制（CR）的方式上调 Sirtuin 1（SIRT1）。SIRT1 特异性 siRNA 和 SIRT1 抑制剂 EX527 减弱了 DAPA 治疗的抗钙化作用。DAPA 还可以驱动 SIRT1 介导的去乙酰化和随后的缺氧诱导因子-1α（HIF-1α）降解。使用氯化钴和蛋白酶体抑制剂 MG132 来维持 HIF-1α 的稳定性减轻了 DAPA 的抗钙化活性。这些分析表明，DAPA/SGLT2/SIRT1 轴可能代表一种治疗血管钙化的可行新方法，为 SGLT2 抑制剂如何帮助预防和治疗血管钙化提供了新的见解。
