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. 2023 Sep 1;13(1):14341.
doi: 10.1038/s41598-023-40795-1.

Proteomic and phosphoproteomic analyses of myectomy tissue reveals difference between sarcomeric and genotype-negative hypertrophic cardiomyopathy

Ramin Garmany  1   2 , J Martijn Bos  2   3   4 , Surendra Dasari  5 , Kenneth L Johnson  6 , David J Tester  2 , John R Giudicessi  3 , Cristobal Dos Remedios  7 , Joseph J Maleszewski  3   8 , Steve R Ommen  3 , Joseph A Dearani  9 , Michael J Ackerman  10   11   12   13
Affiliations

Proteomic and phosphoproteomic analyses of myectomy tissue reveals difference between sarcomeric and genotype-negative hypertrophic cardiomyopathy

Ramin Garmany et al. Sci Rep. .

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetically heterogenous condition with about half of cases remaining genetically elusive or non-genetic in origin. HCM patients with a positive genetic test (HCMSarc) present earlier and with more severe disease than those with a negative genetic test (HCMNeg). We hypothesized these differences may be due to and/or reflect proteomic and phosphoproteomic differences between the two groups. TMT-labeled mass spectrometry was performed on 15 HCMSarc, 8 HCMNeg, and 7 control samples. There were 243 proteins differentially expressed and 257 proteins differentially phosphorylated between HCMSarc and HCMNeg. About 90% of pathways altered between genotypes were in disease-related pathways and HCMSarc showed enhanced proteomic and phosphoproteomic alterations in these pathways. Thus, we show HCMSarc has enhanced proteomic and phosphoproteomic dysregulation observed which may contribute to the more severe disease phenotype.

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Conflict of interest statement

MJA is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. MJA and Mayo Clinic have a royalty/equity relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. However, none of these entities have contributed to this study in any manner. The remaining authors have no conflicts to declare.

Figures

Figure 1
Figure 1
Comparison of gene ontology (GO) biological processes altered between HCMSarc and HCMNeg. (A) Most up-regulated gene ontology (GO) biological processes in the proteome using gene set enrichment analysis (GSEA). (B) Most down-regulated GO biological processes in proteome using GSEA. (C) Most altered GO biological processes in phosphoproteome using GSEA.
Figure 2
Figure 2
Comparison of pathways altered between HCMSarc and HCMNeg. (A) Most statistically altered pathways (largest-log [BH p-value]) in proteome. (B) Top up- and down-regulated pathways in proteome. (C) Most statistically altered phosphorylation (largest-log [BH p-value]) of pathways. (D) Top activated and inactivated pathways based on phosphorylation (z-score ≥|1|). *Regulation of the epithelial mesenchymal transition by growth factors pathway was shortened.
Figure 3
Figure 3
Altered diseases and functions in proteome and phosphoproteome identified using ingenuity pathway analysis.
Figure 4
Figure 4
Commonalities and differences in the proteome and phosphoproteome of HCMSarc and HCMNeg. (A) Venn diagram comparing differentially expressed proteins (DEPs) between different comparisons. (B) Venn diagram comparing differentially phosphorylated proteins (DPPs) between different comparisons. (C) Heatmap showing directionality of differentially expressed proteins (DEPs) altered in both HCMSarc and HCMNeg compared with controls. (D) Heatmap showing directionality of differentially phosphorylated proteins (DPPs) altered in both HCMSarc and HCMNeg compared with controls. Log2fc, log2 fold change.
Figure 4
Figure 4
Commonalities and differences in the proteome and phosphoproteome of HCMSarc and HCMNeg. (A) Venn diagram comparing differentially expressed proteins (DEPs) between different comparisons. (B) Venn diagram comparing differentially phosphorylated proteins (DPPs) between different comparisons. (C) Heatmap showing directionality of differentially expressed proteins (DEPs) altered in both HCMSarc and HCMNeg compared with controls. (D) Heatmap showing directionality of differentially phosphorylated proteins (DPPs) altered in both HCMSarc and HCMNeg compared with controls. Log2fc, log2 fold change.
Figure 5
Figure 5
Commonalities and differences in the proteome and phosphoproteome of HCMSarc and HCMNeg continued. (A) Venn diagram comparing pathways altered in proteome between different comparisons. (B) Venn diagram comparing pathways with altered phosphorylation between different comparisons. (C) Heatmap showing directionality of pathways altered in both HCMSarc and HCMNeg compared with controls. (D) Heatmap showing directionality of phosphorylated pathways altered in both HCMSarc and HCMNeg compared with controls.
Figure 5
Figure 5
Commonalities and differences in the proteome and phosphoproteome of HCMSarc and HCMNeg continued. (A) Venn diagram comparing pathways altered in proteome between different comparisons. (B) Venn diagram comparing pathways with altered phosphorylation between different comparisons. (C) Heatmap showing directionality of pathways altered in both HCMSarc and HCMNeg compared with controls. (D) Heatmap showing directionality of phosphorylated pathways altered in both HCMSarc and HCMNeg compared with controls.
Figure 6
Figure 6
Proteome of sarcomere-positive HCM and sarcomere-negative HCM have differences in disease specific pathways with most differences between them being more severe in sarcomere-positive HCM.
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