Multi-Omics Analysis Reveals the Role of Sigma-1 Receptor in a Takotsubo-like Cardiomyopathy Model

Figures

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  Figure 1. ISO induced TTS-like cardiac damage in WT mice. (A) Protocol scheme of the experiment. (B) Representative echocardiography images. (C,D) Indices of cardiac function: EF, FS (%) in mice. n = 5–6. Student’s t-test was used for statistical analysis. * p < 0.05.

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  Figure 2. Gut microbial alteration in TTS mice. (A,B) Shannon index and Simpson index of α-diversity analysis. (C) PCoA plot of the gut microbiome. (D,E) The composition of the gut microbiome at the phylum and genus levels. (F–H) Significance test of differential bacteria at the genus level using the Wilcoxon rank-sum test, followed by the FDR-corrected post hoc test. * p < 0.05, ** p < 0.01. (I) Correlation analysis between differential bacteria (top 40 at the genus level) and indices of cardiac dysfunction. Red represents a positive relation, while blue represents a negative relation. The depth of color corresponds to the degree of connection.

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  Figure 3. Metabolite variation in TTS mice. (A) PLS-DA score plot between the WT_C and WT_ISO groups. (B) Volcano plot of differentially abundant metabolites in mouse serum (n = 7 in the WT_C group, n = 8 in the WT_ISO group). (C) Heatmap showing the expression profile and VIP value of metabolites. Butyric acid, tauroursodeoxycholic acid, and taurocholic acid were downregulated in TTS mice. The VIP value was based on OPLS-DA. * p < 0.05, ** p < 0.01, *** p < 0.001. (D) KEGG enrichment analysis using the hypergeometric distribution algorithm. (E) Correlation analysis between differentially abundant metabolites (top 40 VIP) and indices of cardiac dysfunction.

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  Figure 4. Transcriptomic variation in TTS mice. (A) MA plot of the differentially expressed genes (DEGs) between the WT_C and WT_ISO groups. (B) Relative mRNA expression of Sigmar1 was upregulated in TTS mice. p-value was from Student’s t-test. * p < 0.05. (C) The expression of all differentially expressed genes is shown in the heatmap. There was clear hierarchical clustering of samples between groups. (D) Specific potential pathways were selected for illustration in the bar chart of the KEGG enrichment analysis.

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  Figure 5. Sigmar1 knockout induced cardiac damage in female mice. (A) Representative echocardiography images in M-mode. (B,C) Indices of cardiac function: EF, FS (%) in mice. n = 7–8. Student’s t-test was used for statistical analysis. ** p < 0.01. *** p < 0.001.

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  Figure 6. Sigmar1 knockout resulted in alterations in gut microbial composition. (A–D) α-Diversity indices between the WT_C and KO_C groups. Both the richness and diversity of the gut microbiome were increased in the KO_C group. (E) PCoA plot of the gut microbiome. (F,G) The composition of the gut microbiome at the phylum and genus levels. (H–J) Significance test of differential bacteria at the genus level using the Wilcoxon rank-sum test followed by the FDR-corrected post hoc test. * p < 0.05, ** p < 0.01, *** p < 0.001.

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  Figure 7. Sigmarr1 knockout resulted in variation in serum metabolites and the transcriptome of the heart. (A) Score plot of PLS-DA between the WT_C and KO_C groups. (B) Volcano plot of differentially abundant metabolites. (C) Heatmap demonstrating the expression profile and VIP value of metabolites. * p < 0.05. ** p < 0.01. *** p < 0.001. (D) KEGG enrichment analysis using the hypergeometric distribution algorithm. The mTOR signaling and apoptosis pathways were the most significantly enriched. (E) The MA plot of the DEGs. (F) The expression of DEGs is shown in the heatmap. There was clear hierarchical clustering of samples between the WT_C and KO_C groups. (G) Certain potential pathways were selected for illustration in the bar chart of the KEGG enrichment analysis.

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  Figure 8. Sigmar1 knockout aggravated cardiac damage in TTS mice and changed the gut microbial community. (A) Representative echocardiography images in M-mode. (B,C) Indices of cardiac function: EF, FS (%) in mice. n = 8. ** p < 0.01. (D) PCoA at the OTU level of the gut microbiome. (E,F) The composition of the gut microbiome at the phylum and genus levels. There was a noticeable difference in microbial composition. (G) Community heatmap analysis illustrates the detailed abundance of bacteria at the genus level.

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  Figure 9. Sigmar1 knockout changed the gut microbial community in TTS mice. (A–E) Significance test of differential bacteria at the genus level using the Wilcoxon rank-sum test followed by the FDR-corrected post hoc test. * p < 0.05, ** p < 0.01. *** p < 0.001. Lactobacillus, Colidextribacter, Bacteroides, and Dubosiella showed noticeable changes in abundance. (F) Cladogram of communities that had significantly different impacts on sample division by LEfSe analysis. (G) Correlation heatmap between differential bacteria and indices of cardiac dysfunction.

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  Figure 10. Sigmarr1 knockout altered serum metabolites and the heart transcriptome in TTS mice. (A) Score plot of PLS-DA between the WT_ISO and KO_ISO groups. (B) Volcano plot of differentially abundant metabolites. (C) Heatmap demonstrating the expression profile and VIP values of metabolites. (D) KEGG enrichment analysis of differentially abundant metabolites. * p < 0.05, ** p < 0.01, *** p < 0.001. (E) The MA plot of the DEGs. (F) DEGs are shown in the heatmap. Samples between the WT_ISO and KO_ISO groups were found to cluster well. (G) Particular potential KEGG pathways were selected for illustration in the bar chart.