Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: A possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification

Xu, Ran; Huang, Ying; Zhu, Dan; Guo, Jianghong

doi:10.1016/j.freeradbiomed.2022.03.013

Cited by 12 publications

(4 citation statements)

References 26 publications

(36 reference statements)

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“…Long-term high-dose iron stimulation produces intracellular oxidative stress, which can cause ferroptosis and facilitate the osteogenic differentiation of VICs 46 . Thus, intracellular reactive oxygen species (ROS) production and ferroptosis were evaluated in SK@PFe-treated hVICs.…”

Section: Resultsmentioning

confidence: 99%

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation

Chen,

Ren,

Xie

et al. 2024

Nat Commun

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Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790—an anti-calcification drug—to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr−/−) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

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Section: Resultsmentioning

confidence: 99%

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation

Chen,

Ren,

Xie

et al. 2024

Nat Commun

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“…NAFLD exacerbated insulin resistance ( 37 ), caused atherogenic dyslipidemia, inflammation, and increased collagen synthesis, all of which have been implicated in the pathophysiology of valvular calcification ( 5 ). In addition, NAFLD also promoted ferroptosis ( 38 ), which was shown to be one of the main mechanisms of AVC ( 39 ). This further supports the possibility that the toxic systemic effects of NAFLD may be responsible for the observed association between NAFLD and the risk of AVC incidence.…”

Section: Discussionmentioning

confidence: 99%

Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease

Hao,

Zeng,

Lin

et al. 2024

Front. Endocrinol.

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BackgroundNon-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS).MethodsA post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion.ResultsAfter adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03–2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01–1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66–4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01–1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes.ConclusionsNAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion.

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“…It has been implicated in various conditions, examples of cardiovascular diseases that can be influenced by ferroptosis include atherosclerosis, drug-related heart failure, myocardial ischemia-reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia, and diabetic cardiomyopathy [18]. In 2022, Xu et al reported the association between ferroptosis and the progression of CAVD for the first time [19]. In our experiments, we observed that ferroptosis is involved in Nesfatin-1's attenuation of osteogenic differentiation in AVICs.…”

Section: Introductionmentioning

confidence: 99%

Nesfatin-1 mitigates calcific aortic valve disease via suppressing ferroptosis mediated by GSH/GPX4 and ZIP8/SOD2 axes

Wang,

Gu,

Bian

et al. 2024

Preprint

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Objective: Calcific aortic valve disease (CAVD) is a prevalent condition in the elderly population, lacking effective medical treatments. Nesfatin-1, a hypothalamic peptide generated from Nucleobindin 2 processing, has been implicated in both physiological and pathological calcification. In this study, we aimed to investigate the role of Nesfatin-1 in facilitating the transformation of aortic valve interstitial cells (AVICs) in relation to CAVD. Methods and Results: In vitro experiments demonstrated that Nesfatin-1 treatment attenuated osteogenic differentiation of AVICs, while in vivo studies showed that it slowed down CAVD progression. RNA-sequencing analysis of AVICs treated with or without Nesfatin-1 revealed enrichment of the Ferroptosis pathway among the top 15 Kyoto Encyclopedia of Genes and Genomes pathways. Further investigations confirmed increased ferroptosis in calcified valves and osteoblast-like AVICs, with Nesfatin-1 treatment reducing ferroptosis in AVICs. Among the genes involved in the Ferroptosis pathway, ZIP8 exhibited the most significant change upon Nesfatin-1 treatment. Silencing ZIP8 enhanced ferroptosis and osteogenic differentiation in AVICs. Additionally, silencing ZIP8 reduced intracellular Mn2+ concentration, as well as the expression and activity of superoxide dismutase (SOD2). Concordantly, silencing SOD2 further enhanced ferroptosis and osteogenic differentiation in AVICs. Moreover, Nesfatin-1 treatment increased glutathione peroxidase 4 (GPX4) expression and glutathione (GSH) levels in AVICs, as confirmed by Western blotting and GSH concentration estimation. Conclusion: In summary, Nesfatin-1 inhibits osteogenic differentiation of AVICs by attenuating ferroptosis. This reduction in ferroptosis levels is mediated by the GSH/GPX4 and ZIP8/SOD2 axes.

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Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: A possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification

Cited by 12 publications

References 26 publications

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation

Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease

Nesfatin-1 mitigates calcific aortic valve disease via suppressing ferroptosis mediated by GSH/GPX4 and ZIP8/SOD2 axes

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