Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies

Q: What is the clinical evidence from this study?

Population: Calcific aortic valve disease (n=24). Intervention: Cyanate (to induce carbamylation) and Glycylglycine (inhibitor) vs. Model group (high-fat diet alone) and regular diet controls. Primary outcome: Serum PON1 concentration (p=0.0001).

Q: What does this research mean for the field?

Carbamoylated high-density lipoprotein accelerates calcific aortic valve disease progression by impairing PON1 antioxidant activity, disrupting endothelial homeostasis, and activating inflammatory and osteogenic signaling. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Min Han; Wang Jiang; Yalong Yang; Ran Chen

doi:10.1515/biol-2025-1367

January 1, 2026Open Life SciencesOpen Access

Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies

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Key result

Cyanate promotes calcific aortic valve disease via PON1 reduction, which glycylglycine partially reverses.

P=0.0001
n=24

Figures

Why the study?

Calcific aortic valve disease is a progressive fibrocalcific illness lacking effective pharmaceutical treatments, and the role of carbamoylated HDL in its progression and molecular pathways is unclear.

Key Points

To investigate whether carbamoylated high-density lipoprotein (C-HDL) drives the progression of calcific aortic valve disease (CAVD) and to determine the underlying molecular pathways.
Male ApoE−/− mice fed a high-fat diet were divided into a CAVD model group, a cyanate-treated group, and a cyanate plus glycine (Gly) inhibitor group for 12 weeks, with regular diet C57BL/6 mice serving as blank controls.
Aortic valve calcification, serum paraoxonase-1 (PON1), CD31, phosphorylated NF-κB p65 (p-p65), NOTCH1, and RUNX2 were evaluated in vivo.
Human aortic valve interstitial cells (AVICs) were treated with PBS or C-HDL (75 μg/mL) for 8 hours and analyzed using RNA sequencing, pathway enrichment, and qRT-PCR validation.
Cyanate exposure significantly lowered serum PON1 levels compared to the model group (P = 0.0001) and increased von Kossa-positive calcium deposits, while Gly intervention reversed these effects (P = 0.0404 for PON1).
Cyanate treatment elevated CD31 area (P = 0.00114) and significantly increased valvular p-p65, NOTCH1, and RUNX2 protein expression (P < 0.05), which were partially mitigated by Gly intervention (P < 0.05).
Transcriptomic profiling in AVICs identified 270 differentially expressed genes enriched in NF-κB and cytoskeletal pathways, with qRT-PCR confirming the downregulation of five hub genes: BIRC6, PIK3R1, ATM, IFIH1, and DDX58.

Structured PICO

P

Population

24 male mice (18 ApoE-/- and 6 C57BL/6) and human aortic valve interstitial cells were evaluated over 12 weeks to assess the role of carbamoylated high-density lipoprotein in calcific aortic valve disease.

I

Intervention

In vivo: Cyanate-containing drinking water (1 mg/L) with or without intraperitoneal glycylglycine (Gly) 500 mg/kg for 12 weeks. In vitro: Carbamoylated high-density lipoprotein (C-HDL) 75 μg/mL for 8 hours.

C

Comparator

In vivo: Model group receiving high-fat diet only, and blank controls on regular diet. In vitro: PBS control.

O

Outcome

Serum PON1 levels, aortic valve calcium deposition (von Kossa staining), CD31, p-p65, NOTCH1, and RUNX2 expression, and transcriptomic changes in AVICs.surrogate

Main Result

p-value: p=0.0001

Carbamoylated HDL may accelerate calcific aortic valve disease through endothelial dysfunction and inflammatory-osteogenic signaling, identifying new potential therapeutic targets.

Limitations

PON1 enzyme activity and HDL carbamylation were not measured directly.
Endothelial activation or damage cannot be determined only by CD31 expression.
Only total NOTCH1, p-p65, and RUNX2 were included in the Western blot results; further pathway markers and functional inhibition studies are required.
Potential hub genes identified via RNA-seq and network analysis need to be mechanistically validated.
Generalizability is constrained by the comparatively small animal sample size.
neither PON1 enzyme activity nor HDL carbamylation were measured
endothelial activation or damage cannot be determined only by CD31 expression
only total NOTCH1, p-p65, and RUNX2 were included in the Western blot results; further pathway markers and functional inhibition studies are required
RNA-seq and network analysis were used to identify the potential hub genes, which need to be mechanistically validated
generalizability is constrained by the comparatively small animal sample size

Implication

Should not change CAVD management; leaves open C-HDL as a therapeutic target in humans.

Abstract

Calcific aortic valve disease (CAVD) is a progressive fibrocalcific illness for which no effective pharmaceutical treatment exists. This study investigated whether carbamoylated high-density lipoprotein (C-HDL), a defective type of HDL that can develop during inflammation, contributes to CAVD progression and the involved molecular pathways. Male ApoE −/− mice were divided into three groups: CAVD model, cyanate-treated, and inhibitor, and analyzed after 12 weeks. C57BL/6 mice on a regular diet served as blank controls. Serum paraoxonase-1 (PON1), aortic valve calcification, cluster of differentiation 31 (CD31), phosphorylated nuclear factor kappa B p65 (p-p65), NOTCH receptor 1 (NOTCH1), and runt-related transcription factor 2 (RUNX2) were evaluated. In parallel, using RNA sequencing (RNA-seq), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, protein-protein interaction (PPI) network analysis, and quantitative real-time polymerase chain reaction. Cyanate treatment reduced serum PON1 levels, increased von Kossa-positive calcium deposition, and raised CD31, p-p65, NOTCH1, and RUNX2 levels compared with the model group, but Gly partially corrected these effects. Transcriptomic research identified 270 C-HDL-associated differentially expressed genes (DEGs) enriched in pathways associated with inflammatory signaling and NF-κB activity. Five potential hub genes (BIRC6, PIK3R1, ATM, IFIH1, and DDX58) were discovered and verified using qRT-PCR. These data show that C-HDL may accelerate CAVD by disrupting valve endothelial homeostasis and stimulating inflammatory signaling, and they identify potential molecular targets for future functional validation.

Discussion

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Cite This Study

Han et al. (2026) studied Calcific aortic valve disease (n=24). Cyanate (to induce carbamylation) and Glycylglycine (inhibitor) vs. Model group (high-fat diet alone) and regular diet controls was evaluated on Serum PON1 concentration (p=0.0001).

synapsesocial.com/papers/6ad0fcf33afa093ea9ad0083 https://doi.org/10.1515/biol-2025-1367

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Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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