Potential ferroptosis key genes in calcific aortic valve disease

Abstract

Calcific aortic valve disease (CAVD) is a highly prevalent condition that comprises a disease continuum, ranging from microscopic changes to profound fibro-calcific leaflet remodeling, culminating in aortic stenosis, heart failure, and ultimately premature death. Ferroptosis has been hypothesized to contribute to the pathogenesis of CAVD. We aimed to study the association between ferroptosis genes and CAVD and reveal the potential roles of ferroptosis in CAVD. CAVD-related differentially expressed genes (DEGs) were identified via bioinformatic analysis of Datasets GSE51472 and GSE12644 obtained from Gene Expression Omnibus. A ferroptosis dataset containing 259 genes was obtained from the Ferroptosis Database. We then intersected with CAVD-related DEGs to identify the ferroptosis DEGs. Subsequently, protein–protein interaction networks and functional enrichment analyses were performed for ferroptosis DEGs. Then, we used miRWalk3.0 to predict the target pivotal microRNAs. An in vitro model of CAVD was constructed using human aortic valve interstitial cells. The qRT-PCR and western blotting methods were used to validate the ferroptosis DEGs identified by the microarray data. A total of 21 ferroptosis DEGs in CAVD containing 12 upregulated and nine downregulated genes were identified. The results of the Gene Set Enrichment Analysis (GSEA) and analysis of the KEGG pathway by WebGestalt indicated that the ferroptosis DEGs were enriched in six signaling pathways among which NAFLD (including IL-6, BID, and PRKAA2 genes) and HIF-1 (including IL-6, HIF-1, and HMOX1 genes) signaling pathways were also verified by DAVID and/or Metascape. Finally, the in vitro results showed that the mRNA and protein expression levels of IL-6, HIF-1α, HMOX1, and BID were higher, while the levels of PRKAA2 were lower in the Pi-treated group than those in the control group. However, the addition of ferrostatin-1 (a selective ferroptosis inhibitor) significantly reversed the above changes. Therefore, IL-6, HIF-1α, HMOX1, BID, and PRKAA2 are potential key genes closely associated with ferroptosis in CAVD. Further work is required to explore the underlying ferroptosis-related molecular mechanisms and provide possible therapeutic targets for CAVD.

Identification of key ferroptosis genes in diabetic retinopathy based on bioinformatics analysis

“…Ferroptosis is a new mode of programmed cell death involving the accumulation of lipid peroxides that damage the cell membrane and is considered different from apoptosis, necrosis, and autophagy [ 16 ]. Li et al used bioinformatics methods to identify the key genes of ferroptosis-related to Calcic aortic valve disease and proved in vitro that these hub genes are differentially expressed in Calcic aortic valve disease and normal people [ 17 ]. Previous studies have shown that ferroptosis is associated with aging retinopathy [ 18 ], light-induced retinal degeneration [ 19 ], retinitis pigmentosa [ 20 ], and glaucoma damage [ 21 ].…”

Differential expression profiles and functional analysis of long non-coding RNAs in calcific aortic valve disease

“…It is interesting to note that the lncRNA AC243829.4 is the ferroptosis-related lncRNA. Despite still being in its infancy, ferroptosis showed a wide range of perspectives in valve calcification [ 38 , 39 ].…”

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

“…It is identified that the endothelial cells play crucial impacts in the calcification process through the EndMT [ 91 ]. Multiple pathways are involved in this process including the signaling pathways involved in hypoxia and inflammation, such as the transforming growth factor beta (TGF-β) signaling pathway [ 92 ], and the Wnt signaling pathway [ 93 , 94 ].…”