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Updated: Jun 26, 2025
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
Sodium-glucose cotransporter 2 inhibitors attenuate vascular calcification by suppressing endoplasmic reticulum
Shaofa Wu1, Xiaolin Luo2, Yang Chen2
1Department of Cardiology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China; Department of Nephrology, Youyang Hospital, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 409800, China.
Aims:
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.
Methods And 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.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce vascular calcification by downregulating TXNDC5, preventing Runx2 degradation. These findings suggest SGLT2 inhibitors are promising for preventing and treating vascular calcification.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Nephrology
Background:
- Vascular calcification significantly increases cardiovascular event risk, yet effective treatments remain limited.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors, primarily used for diabetes, show potential cardiovascular benefits, including effects on vascular calcification.
- The precise mechanisms by which SGLT2 inhibitors impact vascular calcification are not fully understood.
Purpose of the Study:
- To investigate the protective effects of SGLT2 inhibitors against vascular calcification.
- To elucidate the underlying molecular mechanisms involved in SGLT2 inhibitor-mediated vascular calcification prevention.
Main Methods:
- Analysis of coronary CT angiography data from 1554 type 2 diabetes patients to correlate SGLT2 inhibitor use with calcification scores.
- In vivo studies using rodent models of chronic kidney disease and Western diet-induced atherosclerosis to assess the impact of dapagliflozin (DAPA) on vascular calcification.
- In vitro studies using vascular smooth muscle cells (VSMCs) to examine DAPA's effects on osteogenic transdifferentiation, TXNDC5 expression, Runx2 stability, and endoplasmic reticulum (ER) stress.
- Transcriptome profiling to identify key molecular players, followed by rescue experiments to validate findings.
- Validation of class effects using empagliflozin in relevant calcification models.
Main Results:
- SGLT2 inhibitor use was associated with lower coronary artery calcification scores in patients with type 2 diabetes.
- Dapagliflozin (DAPA) significantly reduced both intimal and medial vascular calcification in multiple preclinical models.
- DAPA inhibited VSMC osteogenic transdifferentiation by downregulating TXNDC5, which stabilized Runx2 and reduced its proteasomal degradation.
- DAPA ameliorated ER stress and oxidative stress, leading to decreased TXNDC5 expression.
- Empagliflozin demonstrated similar class effects on vascular calcification.
Conclusions:
- SGLT2 inhibitors effectively ameliorate vascular calcification by inhibiting ER stress-induced TXNDC5 upregulation and promoting Runx2 proteasomal degradation.
- These findings highlight a novel mechanism for SGLT2 inhibitors in cardiovascular protection.
- SGLT2 inhibitors represent a potential therapeutic strategy for the prevention and treatment of vascular calcification.
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