Multi-species transcriptomic data analysis reveal three candidate genes, responsible for the transition from compensated left ventricle hypertrophy to heart failure
Abstract Introduction Heart failure (HF) is the common final event for a wide spectrum of compensated left ventricle hypertrophy (LVH), including hypertrophic cardiomyopathy, hypertension, aortic stenosis and aortic coarctation. Despite its importance, the transition from hypertrophy to HF in humans...
| Published in: | European Heart Journal |
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| Main Authors: | , , |
| Format: | Article in Journal/Newspaper |
| Language: | English |
| Published: |
Oxford University Press (OUP)
2021
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| Subjects: | |
| Online Access: | http://dx.doi.org/10.1093/eurheartj/ehab724.3292 https://academic.oup.com/eurheartj/article-pdf/42/Supplement_1/ehab724.3292/41056781/ehab724.3292.pdf |
| Summary: | Abstract Introduction Heart failure (HF) is the common final event for a wide spectrum of compensated left ventricle hypertrophy (LVH), including hypertrophic cardiomyopathy, hypertension, aortic stenosis and aortic coarctation. Despite its importance, the transition from hypertrophy to HF in humans is poorly understood. In this study, we aimed to find a molecular signature for the transition from compensated hypertrophy to decompensated HF conserved within species and disease induction methods. Methods Four datasets, containing gene expression data of hypertrophy and heart failure samples, were selected from GEO data repository. The selected datasets include three different species: Rattus norvegicus (GSE4286 and GSE47495), Canis lupus familiaris (GSE5247) and Cavia porcellus (GSE78077); with different models of left ventricle hypertrophy (pressure-overload, genetic, and both). The CEL files containing the expression data were analyzed using the Transcriptome Analysis Console 4.0 (TAC 4.0.2.15, Applied Biosystems). To identify differentially expressed genes a p-value cutoff of 0.05 was applied. Results The lists of DEGs obtained in the comparison hypertrophy versus HF, in each dataset, were uniformized to human identifiers and merged, resulting in a list containing 8307 genes. Most of the genes were differentially expressed in only one dataset (6252, 75.3%). DEGs present in two datasets were 1850 (22.3%), in three datasets 202 (2.4%), and finally, present in all datasets were only 3 genes. The first gene identified was CDKS1B, which belongs to a family of proteases related to the cell cycle. CKS1B upregulation activates the STAT3 and MEK/ERK pathways and promotes cell proliferation. Indeed, negative regulation of the MEK/ERK reduces cardiac hypertrophy induced by pressure overload. Secondly, type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate, and plays an important role in inflammatory response and autophagy. However, its role in the heart remains unknow. Lastly, the adipokine MEDAG was also differentially expressed in HF. Its role in myocyte metabolism is not defined but may parallel nutrient uptake role seen in adipose and reflect reliance on lipid oxidation. Conclusions We identified three genes that are differentially expressed in HF compared to compensated hypertrophy, involved in cell proliferation, autophagy, inflammation and lipid metabolism. This data requires confirmation in human studies. Such advance would be an important step toward identifying those risk factors, especially genetic variation, that predispose individuals to develop HF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FCT Portugal |
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