In this article, the main pathogenesis and biomarkers of heart failure were obtained by screening the DEGs of clinical heart failure expression profile GSE26887 and analyzing the GO function, KEGG pathway enrichment and PPI. The occurrence of heart failure is the result of multi-factors and genes. Therefore, the exploration of the molecular mechanism of heart failure is very important for the occurrence and development of heart failure. The target genes of heart failure have been widely predicted by microarray and the high-throughput sequencing technology, most research has focused on animal experiments for heart failure, and the present study was based on isolated left ventricular myocardial tissue from patients with clinical heart failure, through bioinformatics method to analyze the raw data and identify 236 DEGs. Further information of 236 DEGs was mined based on functions enrichment and signaling pathways, respectively.
This study is to explore the underlying mechanism of action on patients with heart failure. We analyzed the DEGs between patients with heart failure and control by multiple bioinformatics methods including enrichment, KEGG analysis and PPI analysis. According to GEO database, we analyzed the chip GSE26887 making use of R software package, and the DEGs 236 were screened out. PPI analysis showed that IL6, CD44 and SOCS3 genes were key factors for patients with heart failure. A pleiotropic cytokine, IL6, could activate immune cells to protect the host from damage in the short term, however, it became pathogenic to the host in a condition of remaining long-term activation. Chronically elevated IL6 levels result in chronic inflammation and fibrotic disorders for the heart tissue. Studies had shown that elevated serum IL6 levels may be a potential prognostic predictor associated with heart disease, such as heart failure, myocardial infarction, and angina[32–35]. CD44 is a multifunctional transmembrane glycoprotein, which interacts with hyaluronic acid to mediate the migration and proliferation of endothelial cells, macrophages, fibroblasts and other cell types. Meanwhile, it was involved in the stimulation of
Tumor necrosis factorα/Nuclear-factor-kappa-B (TNFα/NFkB) signaling pathway to promote the production of inflammation and development of cardiac fibrosis[36–38], causing the remodeling of extracellular matrix. Excessive remodeling of the extracellular matrix was likely to result in heart failure. Therefore, CD44 may be considered as a novel potential therapeutic target for the treatment of heart failure. Another gene, SOCS3, is one of the negative regulators of gp130/JAK/STAT3 signaling pathway, indicating that SOCS3 is closely related to STAT3. Activation of STAT3 signaling pathway is one of the important mechanisms of myocardial hypertrophy, and myocardial remodeling is a compensation method adopted by the body under the condition of overload anterior and posterior of cardiomyocytes, which is one of the important mechanisms of heart failure. However, negative feedback regulation of SOCS3 slows down the development of heart failure by inhibiting the overexpression of STAT3. In addition, IL6 can also reduce the expression of SOCS3 by activating STAT3[39, 40], therefore, SOCS3 may be a new potential target for the treatment of heart failure. According to the above discussion,IL6༌CD44 and SOCS3 have a bearing on the remodeling of the extracellular matrix, which act as markers of heart failure to provide a reference basis for the early prevention and treatment of heart failure.
Further analysis of the DEGs revealed that the function was mainly involved in extracellular space, extracellular matrix, extracellular matrix organization by GO enrichment analysis. Extracellular matrix alterations are closely related to cardiac remodeling, which play a pivotal role in the development and evolution of heart failure. IL6, CD44 and SOCS3 can impact the alterations of the extracellular matrix, so they are crucial factors leading to heart failure. KEGG pathway analysis showed the major role of ECM-receptor interaction, drug metabolism - cytochrome P450 and pathogenic Escherichia coli infection pathways in heart failure. Studies have indicated that extracellular matrix is considered as an important role in cardiac remodeling. CD44 is a cell-surface receptor of extracellular matrix proteins, which may serve as an underlying target for inhibiting extracellular matrix remodeling and slowing down the development of heart failure. Other pathways are cytochrome P450 and pathogenic Escherichia coli infection associated with heart failure, among which cytochrome P450 is a multigene superfamily of enzymes that plays an important role for progression and prognosis of heart failure, such as cardiac CYP2A, CYP1B, CYP2B and CYP2E mRNA levels, which are related to cytochrome P450, usually increase in heart failure. Moreover, pathogenic Escherichia coli infection is also associated with the progression of heart failure in patients, which can impair tight junctions and perturbs intestinal barrier function, possibly leading to intestinal flora disorders. Growing evidence shows that dysbiosis of gut microbiota has an underlying connection with heart failure [45–47], which can contribute to the body inflammation that accelerates the deterioration of heart failure. Therefore, gut microbiota can be considered as potential therapeutic targets for further research on the treatment of heart failure. Through the above analysis of the major genes and pathways of heart failure, it can be seen that inflammation and the alterations extracellular matrix play a major role in the progression of heart failure. Further research is needed to bring insight into the specific mechanisms of heart failure.