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Published on: April 24, 2021
Endoplasmic reticulum stress-related gene expression causes the progression of dilated cardiomyopathy by inducing
Jinhao Chen1,2, Xu Yang1,2, Weiwen Li1,2
1Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Insights
Endoplasmic reticulum stress (ERS)-induced apoptosis plays a role in dilated cardiomyopathy (DCM). Four key genes (MX1, MYH6, TESPA1, THBS4) are dysregulated in DCM, offering new insights into disease mechanisms.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Cellular Stress Response
Background:
- Endoplasmic reticulum stress (ERS)-induced apoptosis is implicated in dilated cardiomyopathy (DCM) pathogenesis.
- The precise molecular mechanisms underlying ERS in DCM remain incompletely understood.
Purpose of the Study:
- To identify and characterize ERS-related genes involved in the development of DCM.
- To elucidate the molecular pathways linking ERS-induced apoptosis to DCM pathogenesis.
Main Methods:
- Integrated analysis of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and endoplasmic reticulum stress-related genes (ERGs).
- Identification of key genes at the intersection of these datasets.
- Analysis of gene co-expression networks, competitive endogenous RNA (ceRNA) interactions, and potential environmental targets.
Main Results:
- Eight genes were identified at the intersection of DEGs, WGCNA modules, and ERGs, associated with immunity and angiogenesis.
- Four genes (MX1, MYH6, TESPA1, THBS4) were specifically linked to apoptosis in DCM, with distinct proposed roles in viral response, calcium handling, inflammation, and sarcomere function.
- XIST was identified as a key regulator in a ceRNA network affecting MX1 and THBS4; environmental toxins like BPA and VPA were found to target MX1, MYH6, and THBS4.
Conclusions:
- Four ERS-related genes (MX1, MYH6, TESPA1, THBS4) are significantly dysregulated in DCM and associated with apoptosis.
- These findings enhance the understanding of ERS-induced apoptosis's role in DCM development.
- The identified genes and pathways provide potential targets for future therapeutic strategies in DCM.
Abstract:
Background: Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the molecular mechanism involved has not been fully characterized. Results: In total, eight genes were obtained at the intersection of 1,068 differentially expressed genes (DEGs) from differential expression analysis between DCM and healthy control (HC) samples, 320 module genes from weighted gene co-expression network analysis (WGCNA), and 2,009 endoplasmic reticulum stress (ERGs). These eight genes were found to be associated with immunity and angiogenesis. Four of these genes were related to apoptosis. The upregulation of MX1 may represent an autocompensatory response to DCM caused by a virus that inhibits viral RNA and DNA synthesis, while acting as an autoimmune antigen and inducing apoptosis. The upregulation of TESPA1 would lead to the dysfunction of calcium release from the endoplasmic reticulum. The upregulation of THBS4 would affect macrophage differentiation and apoptosis, consistent with inflammation and fibrosis of cardiomyocytes in DCM. The downregulation of MYH6 would lead to dysfunction of the sarcomere, further explaining cardiac remodeling in DCM. Moreover, the expression of genes affecting the immune micro-environment was significantly altered, including TGF-β family member. Analysis of the co-expression and competitive endogenous RNA (ceRNA) network identified XIST, which competitively binds seven target microRNAs (miRNAs) and regulates MX1 and THBS4 expression. Finally, bisphenol A and valproic acid were found to target MX1, MYH6, and THBS4. Conclusion: We have identified four ERS-related genes (MX1, MYH6, TESPA1, and THBS4) that are dysregulated in DCM and related to apoptosis. This finding should help deepen understanding of the role of endoplasmic reticulum stress-induced apoptosis in the development of DCM.
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