PDF(Pubmed)
Abstract：
OBJECTIVE: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved.
RESULTS: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models.
CONCLUSIONS: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.
RESULTS: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models.
CONCLUSIONS: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.
摘要：
目的：血管钙化与主要不良心血管事件的发生密切相关，但是缺乏有效的治疗方法。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂是一类新兴的口服降糖药，对代谢和心血管疾病有显著影响。包括最近报道的血管内侧钙化。然而,SGLT2抑制剂在血管钙化中的作用和潜在机制尚未完全阐明.因此，我们旨在进一步确定SGLT2抑制剂是否对血管钙化有保护作用,并研究相关机制.
结果：对1554例2型糖尿病患者的冠状动脉CT血管造影检查显示，SGLT2抑制剂的使用与较低的Agatston钙化评分相关。在维生素D3过量，5/6肾切除术慢性肾脏病诱导的内膜钙化和西方饮食诱导的动脉粥样硬化内膜钙化模型，达格列净(DAPA)显著缓解主动脉血管钙化。此外，我们发现DAPA通过Runx2依赖性血管平滑肌细胞（VSMC）成骨转分化减少血管钙化。转录组分析显示，含有硫氧还蛋白结构域5（TXNDC5）参与DAPA减弱血管钙化。抢救实验表明，DAPA诱导的VSMC中TXNDC5下调阻断了对血管钙化的保护作用。此外，TXNDC5下调破坏了蛋白质折叠依赖性Runx2稳定性，并促进了随后的蛋白酶体降解。此外，DAPA通过改善氧化应激和ATF6依赖性内质网应激下调TXNDC5表达。始终如一，SGLT2抑制剂对血管钙化的类效应在内膜和中层钙化模型中与依帕列净进行了验证.
结论：SGLT2抑制剂通过阻断内质网应激依赖性TXNDC5上调并促进随后的Runx2蛋白酶体降解来改善血管钙化，提示SGLT2抑制剂可能有益于血管钙化的治疗和预防。
结果：对1554例2型糖尿病患者的冠状动脉CT血管造影检查显示，SGLT2抑制剂的使用与较低的Agatston钙化评分相关。在维生素D3过量，5/6肾切除术慢性肾脏病诱导的内膜钙化和西方饮食诱导的动脉粥样硬化内膜钙化模型，达格列净(DAPA)显著缓解主动脉血管钙化。此外，我们发现DAPA通过Runx2依赖性血管平滑肌细胞（VSMC）成骨转分化减少血管钙化。转录组分析显示，含有硫氧还蛋白结构域5（TXNDC5）参与DAPA减弱血管钙化。抢救实验表明，DAPA诱导的VSMC中TXNDC5下调阻断了对血管钙化的保护作用。此外，TXNDC5下调破坏了蛋白质折叠依赖性Runx2稳定性，并促进了随后的蛋白酶体降解。此外，DAPA通过改善氧化应激和ATF6依赖性内质网应激下调TXNDC5表达。始终如一，SGLT2抑制剂对血管钙化的类效应在内膜和中层钙化模型中与依帕列净进行了验证.
结论：SGLT2抑制剂通过阻断内质网应激依赖性TXNDC5上调并促进随后的Runx2蛋白酶体降解来改善血管钙化，提示SGLT2抑制剂可能有益于血管钙化的治疗和预防。
