Sodium-glucose cotransporter 2 inhibitors attenuate vascular calcification by suppressing endoplasmic reticulum protein thioredoxin domain containing 5 dependent osteogenic reprogramming

Redox Biology, Год журнала: 2024, Номер 73, С. 103183 - 103183

Опубликована: Май 13, 2024

Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors an emerging category oral hypoglycemic drugs that have displayed marked effects on metabolic and diseases, including recently reported vascular medial calcification. However, roles underlying mechanisms SGLT2 in not been fully elucidated. Thus, we aimed further determine whether protect against investigate involved. A computed tomography angiography investigation coronary arteries from 1554 patients with type diabetes revealed inhibitor use was correlated a lower Agatston score. In vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease -induced Western diet-induced atherosclerotic intimal models, dapagliflozin (DAPA) substantially alleviated aorta. Furthermore, showed DAPA reduced via Runx2-dependent osteogenic transdifferentiation smooth muscle cells (VSMCs). Transcriptome profiling thioredoxin domain containing 5 (TXNDC5) involved attenuation by DAPA. Rescue experiments DAPA-induced TXNDC5 downregulation VSMCs blocked protective effect disrupted protein folding-dependent Runx2 stability promoted subsequent proteasomal degradation. Moreover, downregulated expression amelioration oxidative stress ATF6-dependent endoplasmic reticulum stress. Consistently, class were validated empagliflozin models. ameliorate through blocking stress-dependent upregulation promoting degradation, suggesting potentially beneficial for treatment prevention.

Язык: Английский

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Impact of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and arterial remodeling

World Journal of Cardiology, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 21, 2025

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition glucose reabsorption in proximal renal tubules, consequently augmenting urinary excretion and attenuating blood levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways which diverse SGLT-2 beneficially modulate pulmonary vascular cells arterial remodeling. Specifically, these exhibit promising potential enhancing endothelial cell function, suppressing smooth muscle proliferation migration, reversing remodeling, maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate mechanisms by enhance function reverse thereby offering novel therapeutic perspectives for diseases.

Язык: Английский

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Longitudinal assessment of coronary plaque regression related to sodium–glucose cotransporter-2 inhibitor using coronary computed tomography angiography

Cardiovascular Diabetology, Год журнала: 2024, Номер 23(1)

Опубликована: Июль 22, 2024

Abstract Background Sodium–Glucose Cotransporter-2 Inhibitor (SGLT2i) is a novel oral drug for treating type 2 diabetes mellitus (T2DM) with demonstrated cardiovascular benefits. Previous studies in apolipoprotein E knockout mice have shown that SGLT2i associated attenuated progression of atherosclerosis. However, whether this effect extends to T2DM patients coronary atherosclerosis real-world settings remains unknown. Methods In longitudinal cohort study using computed tomography angiography (CCTA), who underwent ≥ CCTA examinations at our center between 2019 and 2022 were screened. Eligible had multiple plaques, defined as non-obstructive stenosis baseline not intervened during serial CCTAs. Exclusion criteria included time interval < 12 months, prior treatment, or initiation/discontinuation Plaque volume (PV) percent atheroma (PAV) measured each plaque analysis software. Patients plaques categorized based on therapy compared 1:1 propensity score matching (PSM) analysis. Results The 236 (mean age 60.5 ± 9.5 years; 69.1% male) 435 (diameter 50%, 31.7%). Following treatment median duration 14.6 (interquartile range: 13.0, 20.0) overall, non-calcified, low-attenuation PV PAV significantly decreased, while calcified increased (all p 0.001). Meanwhile, reductions overall PV, non-calcified PAV, greater SGLT2i-treated non-SGLT2i-treated PSM showed was higher (− 11.77 mm 3 vs. 4.33 , = 0.005), 16.96 − 1.81 0.017), 2.83% 3.36%, 0.001), 4.60% 0.70%, 0.003). These findings remained consistent when assessing annual changes compositional PAV. Multivariate regression models even after adjusting risk factors, medications, respectively 0.05). attenuating across subgroups interaction > Conclusions patients, markedly regressed mainly result from significant reduction plaque. Graphical abstract

Язык: Английский

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Danlian-Tongmai formula improves diabetic vascular calcification by regulating CCN3/NOTCH signal axis to inhibit inflammatory reaction

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 6, 2025

Vascular calcification (VC) commonly occurs in diabetes and is associated with cardiovascular disease incidence mortality. Currently, there no drug treatment for VC. The Danlian-Tongmai formula (DLTM) a traditional Chinese medicine (TCM) prescription used diabetic VC (DVC), but its mechanisms of action remain unclear. This study aims to elucidate the effects DLTM on DVC explore underlying action. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was identify metabolites DLTM. A rat model established using streptozotocin (STZ) combined vitamin D3 (VitD3). were evaluated through alizarin red staining, calcium deposition, changes osteogenic contractile markers. specific molecular mechanism treating comprehensively analyzed by transcriptomics, docking vivo experimental verification. We identified 108 major In vivo, high-dose significantly alleviated rats. Transcriptomic analysis showed that markedly altered transcriptomic profile aortas, which regulating CCN3/NOTCH signaling pathway, promoting vascular smooth muscle contraction, inhibiting inflammatory responses. Molecular dynamics simulation demonstrated strong binding interactions between key molecules within including NOTCH1, DLL1, DLL4, hes1, hey1. experiments confirmed could upregulate CCN3, inhibit activation NOTCH ligands DLL1 downstream transcription factors hes1 hey1, reduce release cytokines IL6, IL1β, TNFα. alleviates axis Our research provides basis clinical transformation

Язык: Английский

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SGLT2 Inhibition in Aortic Stenosis

КАРДИОЛОГИЯ УЗБЕКИСТАНА, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Identification of potential biomarkers in cardiovascular calcification based on bioinformatics combined with single-cell RNA-seq and multiple machine learning analysis

Cellular Signalling, Год журнала: 2025, Номер 131, С. 111705 - 111705

Опубликована: Март 1, 2025

Язык: Английский

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Effects of Empagliflozin on Vascular and Skeletal Mineralization in Hyperlipidemic Mice

Vascular Pharmacology, Год журнала: 2024, Номер 155, С. 107376 - 107376

Опубликована: Апрель 30, 2024

Язык: Английский

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Dapagliflozin targets SGLT2/SIRT1 signaling to attenuate the osteogenic transdifferentiation of vascular smooth muscle cells

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Ноя. 9, 2024

Vascular calcification is a complication that frequently encountered in patients affected by atherosclerosis, diabetes, and chronic kidney disease (CKD), characterized the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). At present, there remains pressing lack any effective therapies can treat this condition. The sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) has shown beneficial effects cardiovascular disease. role context calcification, however, largely uncharacterized. Our findings revealed DAPA treatment was sufficient to alleviate vitro vivo calcification. Interestingly, our study demonstrated exerts its anti-calcification on VSMCs directly targeting SGLT2, with overexpression SGLT2 being attenuate these effects. also able limit glucose levels NAD

Язык: Английский

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NLRP3 inflammasomes as a target for hesperidin and diosmin flavonoids in varicose vein disease and its complications

Almanac of Clinical Medicine, Год журнала: 2024, Номер 52(2), С. 95 - 103

Опубликована: Июнь 17, 2024

Varicose vein disease of the lower extremities is an inflammatory disorder with abnormal structure and functional activity venous valves, walls cells, as well infiltrating leukocytes. The abnormally changed varicose are characterized by increased pressure, blood accumulation congestion, ischemia, metabolic energy turnover derangement, which result in clinical manifestations complications, such pain, edema formation trophic ulcers. For many years, flavonoids have been used to treat veins. most effective its hesperidin diosmin, their combinations. review sets forth state-of-the-art knowledge on universal processes playing a leading role pathophysiology cardiovascular disorders, including ones. In recent it has found that one main causes inflammation intracellular protein complexes (inflammasomes), both produce set proinflammatory cytokines responsible for excretion from cells. addition, inflammasomes control development regulated necrosis (pyroptosis) takes part process ulceration. inflammasome can be modified various mechanisms, gene independent synthesis inflammasomal proteins recognized one. It shown inhibit activation key factor NF-kappa B suppress proteins, NOD-like receptor 3 (NLRP3) components, decrease expression NLRP3 receptor, ASC caspase 1, diminish interleukin 1 beta, 6 tumor factor-alpha expression. Thus, this explanation positive effects observed use hesperidin, diosmin combination practice.

Язык: Английский

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Complex actions of sodium glucose transporter-2 inhibitors on lipids, calcific atherosclerosis, and bone density

Current Opinion in Lipidology, Год журнала: 2024, Номер 35(5), С. 253 - 257

Опубликована: Июль 18, 2024

Purpose of review Inhibitors sodium-glucose cotransporter-2 (SGLT2) lower renal glucose reabsorption and, thus, are used to treat patients with type 2 diabetes mellitus. Clinical trials coincidentally showed that SGLT2 inhibitors also benefitted heart failure. This explores the impact on other aspects cardiovascular disease and skeletal health. Recent findings In some, but not all, clinical preclinical studies, found reduce serum levels free fatty acids triglycerides. Their effects total low-density lipoprotein cholesterol cardiac function vary. However, lipid accumulation in liver, kidney, heart, alter expression metabolism genes. Effects acid uptake abdominal fat depots depend location adipose tissue. male, female, mice, atherosclerotic lesions aortic calcium deposition. With respect health, recent literature has reported conflicting associations risks fracture amputation. Summary Studies suggest tissue accumulation, a sex-dependent manner, atherosclerosis vascular calcification. their bone health complex remain be established.

Язык: Английский

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