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

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

PROVIDER: PRJNA1059035 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27384712_1.fastq.gz	Fastqsanger.gz
	SRR27384712_2.fastq.gz	Fastqsanger.gz
	SRR27384713_1.fastq.gz	Fastqsanger.gz
	SRR27384713_2.fastq.gz	Fastqsanger.gz
	SRR27384714_1.fastq.gz	Fastqsanger.gz

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-03 | GSE252268 | GEO

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

Project description: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.

| S-EPMC10792006 | biostudies-literature

Stanniocalcin-1 mediates aortic valve calcification via promoting osteochondrogenic differentiation from valve interstitial cells

Project description:Although calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease, the molecular mechanisms underlying aortic valve calcification remain unknown. Here, we found a significant elevation in stanniocalcin-1 (STC1) expression in the valve interstitial cells (VICs) of calcific aortic valves by combined analysis of our comprehensive gene expression data and microarray datasets reported previously. Immunohistochemical staining showed that STC1 was located around the calcific area in the aortic valves of patients with CAVS. In vitro experiments using inhibitors and siRNA targeting osteoblast differentiation signaling revealed that activation of the Akt/STC1 axis was essential for runt-related transcription factor 2 (RUNX2) induction in the VICs. RNA sequencing and bioinformatics analysis of STC1-knocked down VICs in osteoblast differentiation medium resulted in silencing of the induction of osteoarthritis signaling-related genes, including RUNX2 and COL10A1. STC1 depletion in the murine CAVS model improved aortic valve dysfunction with high peak velocity and valve thickening and suppressed the appearance of osteochondrocytes. STC1-deficient mice also exhibited complete calcification abolishment, although partial valve thickening by aortic valve injury was observed. Our findings suggest that STC1 may be a critical factor in determining valve calcification and a novel target for preventing the transition to severe CAVS with calcification. We analyzed the gene expression profiles of the valve interstitial cells (VICs) isolated from noncalcific and calcific areas in calcific aortic valve stenosis (CAVS) donors using a gene microarray.

2023-12-31 | GSE226781 | GEO

The long non-coding HOTAIR is modulated by cyclic stretch and WNT/beta-CATENIN in human aortic valve cells and is a novel repressor of calcification genes

Project description:Aortic valve calcification is a significant and serious clinical problem for which there are no effective medical treatments. Individuals born with bicuspid aortic valves, 1-2% of the population, are at the highest risk of developing aortic valve calcification. Aortic valve calcification involves increased levels of calcification and inflammatory genes. Bicuspid aortic valve leaflets experience increased strain. The molecular mechanisms involved in the pathogenesis of calcification of BAVs are not well understood, especially the molecular response to mechanical stretch. HOTAIR is a long non-coding RNA (lncRNA) that has been implicated with cancer but has not been studied in cardiac disease. We have found that HOTAIR levels are decreased in BAVs and in human aortic interstitial cells (AVICs) exposed to cyclic stretch. Reducing HOTAIR levels via siRNA in AVICs results in increased expression of calcification genes.

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Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Project description:Calcific aortic valve disease (CAVD) is an increasingly prevalent condition and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show that NO rescues calcification by a S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells (pAVICs) and single cell RNA-seq demonstrated regulation of NOTCH pathway by NO. A unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin proteasome pathway and implicated S-nitrosylation of USP9X in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated aortic valve disease and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a novel mechanism by which S-nitrosylation dependent regulation of ubiquitin-associated pathway prevents CAVD.

2020-12-22 | GSE161123 | GEO

Toll-like receptor 3 mediates calcific aortic valve disease via a conserved mechanism of calcification

Project description:The molecular mechanisms underlying valvular immunaging are not well understood. Toll-like receptors (TLRs) are evolutionary conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Here, we identify TLR3 as a central molecular regulator of calcification in cells exposed to mechanical strain. TLR3 is responsible for the phenotypic switch of valvular interstitial cells (VICs) to bone-forming cells in aortic valves and drives bone formation in vertebrates. Tlr3-/- mice exhibit an osteoporotic phenotype and are protected from CAVD. Moreover, we uncover biglycan (BGN), an extracellular matrix protein released upon mechanical tissue damage, as the first known endogenous TLR3-ligand and provide compelling evidence for receptor-ligand interaction. Our results reveal novel insights in the pathogenesis of CAVD and uncover TLR3 as a potential therapeutic target to prevent cardiovascular calcification and death.

2020-10-01 | GSE138360 | GEO

Toll-like receptor 3 mediates calcific aortic valve disease via a conserved mechanism of calcification

2023-02-01 | GSE223543 | GEO

RNF130 induces aortic valve calcification by promoting SPR ubiquitinationin human valvular interstitial cells

Project description:The study of the RNF130 gene in valve calcification, which correlates the proteome

2025-07-27 | PXD066641 |

The alterations of gene expression in aortic valve from calcific aortic valve disease patients

Project description:Calcification of the aortic valve leads to increased leaflet stiffness resulting in development of calcific aortic valve disease (CAVD); however, the underlying molecular and cellular mechanisms of calcification are poorly understood. Here, we investigated gene expressions in relation to valvular calcification and promotion of CAVD progression.

2016-01-28 | GSE77287 | GEO

ENPP1 deletion and infantile arterial calcification

Project description:The goal of this study was to identify new mutations in the ENPP1 gene that produce infantile arterial calcification and fetal demise. A stillborn (proband) was diagnosed with infantile arterial calcification. Mutations in the ENPP1 gene account for ~80% of the cases of infantile arterial calcification through loss of function in both alleles (recessive inheritance).

2011-01-26 | GSE26860 | GEO

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