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. 2022 Jun 30:9:906753.
doi: 10.3389/fcvm.2022.906753. eCollection 2022.

Ferroptosis and Autophagy-Related Genes in the Pathogenesis of Ischemic Cardiomyopathy

Yue Zheng  1   2   3   4   5 , Wenqing Gao  1   2   3   4   5 , Qiang Zhang  1   2   3   4   5 , Xian Cheng  1   4   5   6 , Yanwu Liu  1   4   5   6 , Zhenchang Qi  1   4   5   6 , Tong Li  1   2   3   4   5   6
Affiliations

Ferroptosis and Autophagy-Related Genes in the Pathogenesis of Ischemic Cardiomyopathy

Yue Zheng et al. Front Cardiovasc Med. .

Abstract

Background: Obesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and mitochondrial respiration. We aimed to investigate the ferroptosis- and autophagy-related differentially expressed genes (DEGs) that might be potential targets for MI progression.

Methods: GSE116250 was analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis- and autophagy-related DEGs. The enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors, and drugs with the hub genes interactions were also predicted. The MI mice model was constructed, and qPCR analysis and single-cell sequencing were used to validate the hub genes.

Results: Utilizing the limma package and the Venn diagram, 26 ferroptosis-related and 29 autophagy-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in the cellular response to a toxic substance, cellular oxidant detoxification, and the IL-17 signaling pathway. The list of autophagy-related DEGs was involved in the regulation of autophagy, the regulation of JAK-STAT signaling pathway, and the regulation of MAPK cascade. In the protein-protein interaction network, the hub DEGs, such as IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, were obtained. After validation using qPCR analysis in the MI mice model and single-cell sequencing, the 10 hub genes can be the potential targets for MI deterioration.

Conclusion: The screened hub genes, IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, may be therapeutic targets for patients with MI and may prevent adverse cardiovascular events.

Keywords: GEO; IL-6; autophagy; ferroptosis; myocardial infarction; pathway enrichment analysis; progression; single cell sequencing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Identification of DEGs in the ischemic myocardiopathy GEO dataset. (A) The normalization of the ischemic myocardiopathy dataset was applied through Log2 Transformation. (B) The gene cluster in PCA loading score. MI, ischemic myocardiopathy; N, control. (C) The heat map of the dataset demonstrated distinguished features between ischemic myocardiopathy and control heart samples. (D) An Upset diagram ofGSE116250 DEGs as well as ferroptosis driver, inducer, inhibitor, marker, and suppressor. (E) A Venn diagram of GSE116250 DEGs and autophagy-related genes.
FIGURE 2
FIGURE 2
The enrichment pathway analysis of ferroptosis-related DEGs. (A) The significant GO and KEGG pathways enriched by ferroptosis-related DEGs using the Xiantao Website. (B) The GO enrichment pathway analysis of ferroptosis-related DEGs using WebGestalt. (C) The Gene Set Enrichment Analysis of ferroptosis-related DEGs using WebGestalt.
FIGURE 3
FIGURE 3
The enrichment pathway analysis of ferroptosis-related DEGs. (A) The pathways network of ferroptosis-related DEGs using Metascape. (B) The enrichment pathway analysis of ferroptosis-related DEGs using Metascape.
FIGURE 4
FIGURE 4
The enrichment pathway analysis of autophagy-related DEGs. (A) The significant GO and KEGG pathways enriched by autophagy-related DEGs using the Xiantao Website. (B) The GO enrichment pathway analysis of autophagy-related DEGs using WebGestalt. (C) The Gene Set Enrichment Analysis of autophagy-related DEGs using WebGestalt.
FIGURE 5
FIGURE 5
The enrichment pathway analysis of autophagy-related DEGs. (A) The pathways network of autophagy-related DEGs using Metascape. (B) The enrichment pathway analysis of autophagy-related DEGs using Metascape.
FIGURE 6
FIGURE 6
The PPI analysis of ferroptosis-related DEGs and autophagy-related DEGs. (A) The PPI analysis of ferroptosis-related DEGs. Red, upregulated genes; blue, downregulated genes. (B) The top10 ferroptosis-related DEGs using MCC. (C) A Venn diagram of ferroptosis-related DEGs using MCC and MCODE analysis module. (D) The PPI analysis of autophagy-related DEGs. Red, upregulated genes; blue, downregulated genes. (E) The top 10 autophagy-related DEGs using MCC. (F) A Venn diagram of autophagy-related DEGs using MCC and the MCODE analysis module.
FIGURE 7
FIGURE 7
The enrichment pathway analysis of ferroptosis- and autophagy-related hub genes. (A) The significant GO and KEGG pathways enriched by ferroptosis- and autophagy-related hub genes using Xiantao Website. (B) The pathways network of the hub genes using the Xiantao Website. (C) The enrichment pathway analysis of the hub genes using Metascape. (D) The pathways network of the hub genes using Metascape.
FIGURE 8
FIGURE 8
Immune infiltration analysis of the hub genes. (A) The score of the immune cells and stroma in GSE116250 is estimated by the xCell. NF, control group; ICM, ischemic myocardiopathy group. (B) The correlation heatmap of the hub genes and cell types with differential immune scores. Red, positive correlation; blue, negative correlation. (C) The correlation heatmap of the hub genes, stroma score, and microenvironment score. Red, positive correlation; blue, negative correlation; white, p > 0.05. Score 1, stroma score; Score 2, microenvironment score.
FIGURE 9
FIGURE 9
qRT-PCR results show the expression levels of ferroptosis-related and autophagy-related hub genes. (A) The related mRNA levels of IL-6, PTGS2, JUN, NQO1, and NOS3 at 3 days after MI. (B) The related mRNA levels of LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1 at 3 days after MI. (C) The related mRNA levels of IL-6, PTGS2, JUN, NQO1, and NOS3 at 1 week after MI. (D) The related mRNA levels of LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1 at 1 week after MI. *p < 0.05; **p < 0.01; ***p < 0.001; ns, not significant.
FIGURE 10
FIGURE 10
The hub genes were highly expressed in the human heart. (A) The overall clustering of cells in the human heart. (B–K) The hub genes were validated to be highly expressed in the human heart, such as IL-6 (B), PTGS2 (C), JUN (D), NQO1 (E), NOS3 (F), LEPR (G), NAMPT (H), CDKN2A (I), CDKN1A (J), and Snai1 (K).
FIGURE 11
FIGURE 11
The hub genes were highly expressed in the postnatal mammalian heart. (A) The overall clustering of cells in the postnatal mammalian heart. (B–J) The hub genes were validated to be highly expressed in the postnatal mammalian heart, such as IL-6 (B), JUN (C), NQO1 (D), NOS3 (E), LEPR (F), NAMPT (G), CDKN2A (H), CDKN1A (I), and Snai1 (J), while there was no PTGS2 expression in the postnatal mammalian heart.
FIGURE 12
FIGURE 12
The hub genes were highly expressed in the human fetal heart. (A) The overall clustering of cells in the human fetal heart. (B–K) The hub genes were validated to be highly expressed in the fetal human heart, such as IL-6 (B), PTGS2 (C), JUN (D), NQO1 (E), NOS3 (F), LEPR (G), NAMPT (H), CDKN2A (I), CDKN1A (J), and Snai1 (K).
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