Integrated microarray analysis to identify potential biomarkers and therapeutic targets in dilated cardiomyopathy

Zhang, Hao; Huo, Junyu; Jiang, Weimin; Shan, Qijun

doi:10.3892/mmr.2020.11145

Cited by 5 publications

(6 citation statements)

References 58 publications

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“…Calumenin can also relieve ER stress-initiated apoptosis in viral myocarditis [ 20 ]. Recently, Zhang et al [ 33 ] identified that calumenin was downregulated in dilated cardiomyopathy. In this study, our results revealed that calumenin levels were decreased in the RV of PAH mice and miR-335-5p antagomir could rescue the downregulation of calumenin, indicating that miR-335-5p might regulate RV remodeling via calumenin.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR-335-5p Contributes to Right Ventricular Remodeling via Calumenin in Pulmonary Arterial Hypertension

Zhang

et al. 2022

BioMed Research International

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Right ventricular (RV) failure determines the prognosis in pulmonary arterial hypertension (PAH), but the underlying mechanism is still unclear. Growing evidence has shown that microRNAs participate in RV remodeling. This study is undertaken to explore the role of miR-335-5p in regulating RV remodeling induced by PAH. Two PAH models were used in the study, including the monocrotaline rat model and hypoxia/su5416 mouse model. miRNA sequencing and RT-qPCR validation identified that miR-335-5p was elevated in the RV of PAH rats. In vitro, miR-335-5p expression was increased after angiotensin II treatment, and miR-335-5p inhibition relieved angiotensin II-induced cardiomyocyte hypertrophy. The luciferase reporter assay showed that calumenin was a target gene for miR-335-5p. Pretreatment with miR-335-5p inhibitors could rescue calumenin downregulation induced by angiotensin II in H9C2 cells. Moreover, intracellular Ca2+ concentration and apoptosis were increased after angiotensin II treatment, and miR-335-5p inhibition decreased intracellular Ca2+ accumulation and apoptosis. Finally, in vivo miR-335-5p downregulation (antagomir miR-335-5p) attenuated RV remodeling and rescued calumenin downregulation under conditions of hypoxia/su5416 exposure. Our work highlights the role of miR-335-5p and calumenin in RV remodeling and may lead to the development of novel therapeutic strategies for right heart failure.

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Section: Discussionmentioning

confidence: 99%

Upregulation of miR-335-5p Contributes to Right Ventricular Remodeling via Calumenin in Pulmonary Arterial Hypertension

Zhang

et al. 2022

BioMed Research International

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“…Myocardial ischemia was excluded by coronary angiography. 15) Subjects with poor compliance, incomplete clinical data, contrast agent sensitivity, and autoimmune diseases were excluded. Additionally, subjects with obvious surgical contraindications were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…[10][11][12][13] Based on this approach, a series of genes and pathways are found to be associated with the prediction and prognosis of dilated cardiomyopathy. 14,15) In addition, studies have shown that immune cell infiltration plays an important role in the occurrence and development of various diseases. 16) For instance, some studies have found biomarkers in patients with acute myocardial infarction 17) or in those with atrial fibrillation with valvular heart disease based on immune cell infiltration.…”

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confidence: 99%

Identification of the Key Genes of Immune Infiltration in Dilated Cardiomyopathy

Qi,

Wang,

et al. 2023

Int. Heart J.

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Dilated cardiomyopathy (DCM) is a common cause of heart failure. In this study, we screened the immune infiltration-related genes associated with DCM to explore the potential molecular mechanisms and provide a basis for the early diagnosis and development of new immunotherapeutic targets. A dataset related to DCM was downloaded from the Gene Expression Omnibus (GEO) database. R software was applied to the genetic differential analysis of patients with DCM and healthy individuals, and the obtained differential expressed genes (DEGs) were screened for differentially expressed immune-related genes (DEIRGs) after comparison with the immune microsatellite database. Gene functional analysis established a protein interaction network (PPI). The immune infiltration in patients with DCM versus normal controls was assessed using the CIBERSORT algorithm, the hub genes were screened using the MOCDE app, and the hubs were validated in multiple datasets. A total of 246 DEGs were screened (adj. P < 0.05 and |logFC| > 0.3), and a total of 170 DEIRGs were compared. Gene Ontology analysis showed significant (adj. P < 0.05) Biological Process entries of 591, Cellular Component of 10, and Molecular Function of 39; Kyoto Encyclopedia of Genes and Genomes showed 20 significant entries, mainly focused on cytokines involved in immune-related response, etc. A protein interaction network comprising 28 hub DEGs was constructed in combination with the PPI network interactions. DEIRG was mainly distributed in the T-cell receptor pathway by immune infiltration detection analysis, and significant changes in central memory T-cells were found by analyzing T-cell-related subpathways, where INSR, HLA-B, IFITM1, and HBEGF were significantly differentially expressed. We selected 632 hospitalized patients for validation and found that INSR and HLA-B expression were associated with DCM development by Nomogram. The expression of HLA-B in peripheral blood T-cells was higher in DCM patients than in the normal group, as verified by qRT-PCR. However, the detailed mechanism needs to be further explored.

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“…Recently, the link between iron overload and cardiovascular disease was attributed to ferroptosis [29,30]. Ferroptosis is an iron-dependent form of programmed cell death involving lipid hydroperoxide accu-mulation [31]. Both in-vitro and in-vivo evidence supports the pathophysiological role of ferroptosis on many forms of cardiovascular dysfunctions [32].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of iron metabolism-linked genes at myocardial tissue and cell levels in dilated cardiomyopathy

Massaiu

Campodonico

Mapelli

et al. 2023

European Journal of Preventive Cardiology

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Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Fondazione Gigi & Pupa Ferrari ONLUS Italian Ministry of Health-Ricerca Corrente. Background Heart failure (HF) is defined as one of the main clinical and public health burdens with multifactorial symptoms and high worldwide prevalence. Dilated cardiomyopathy (DCM) is one of the leading causes of HF and is responsible for over half of all left ventricular assist device implantations and heart transplantations. DCM is regarded as a multiple disease entity linked to a number of genetic, nutritional, inflammatory, infective, metabolic, and environmental causes. Among the metabolic processes associated with HF, iron metabolism disorders, ranging from iron deficiency to iron overload, are gaining attention. However, the understanding of iron mechanisms, at cardiac level, involved in HF and particularly in DCM, remains elusive. Purpose We aim to evaluate the possible dysregulation of iron metabolism-linked genes in DCM, through a quantitative analysis of public myocardial gene expression data at tissue and cell levels. Methods Bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq) datasets, respectively of 436 and 38 left ventricle samples from adult non-failed (NF) and DCM subjects, were retrieved from public studies. We defined a list of 272 genes directly related to intramyocardial iron metabolism and performed the differential gene expression analysis both at whole cardiac tissue level and in cardiomyocytes, fibroblasts, myeloid, endocardial, and endothelial cells. Results In the overall myocardial tissue, we found 44 iron-linked genes differentially expressed between DCM and NF subjects. To better understand iron genes abnormalities in the myocardium of DCM patients we deepened the analysis from tissue to single-cell level. Among the five considered cell types (cardiomyocytes, fibroblasts, myeloid, endocardial, and endothelial cells) at least 9% of iron-linked expressed genes were significantly regulated in DCM when compared to NF. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels (Figure 1), including: 1) imbalance of Fe3+ internalization (SCARA5 down-regulation) and reduction of internal conversion from Fe3+ to Fe2+ (STEAP3 down-regulation), 2) increase of iron consumption to produce hemoglobin (HBA1/2 up-regulation), 3) higher heme synthesis and externalization (ALAS2 and ABCG2 up-regulation), 4) lower cleavage of heme to Fe2+, biliverdin and carbon monoxide (HMOX2 down-regulation), and 5) positive regulation of hepcidin (BMP6 up-regulation). Conclusions In conclusion, the present study provides significant progress in knowledge of iron metabolism changes in DCM disease, which likely have a clinical meaning. Indeed, our data show that regulation of intracellular iron homeostasis is dysfunctional in DCM patients’ cardiac tissues, supporting, but not providing, the hypothesis of a direct effect of iron in the disease progression.

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Integrated microarray analysis to identify potential biomarkers and therapeutic targets in dilated cardiomyopathy

Cited by 5 publications

References 58 publications

Upregulation of miR-335-5p Contributes to Right Ventricular Remodeling via Calumenin in Pulmonary Arterial Hypertension

Upregulation of miR-335-5p Contributes to Right Ventricular Remodeling via Calumenin in Pulmonary Arterial Hypertension

Identification of the Key Genes of Immune Infiltration in Dilated Cardiomyopathy

Dysregulation of iron metabolism-linked genes at myocardial tissue and cell levels in dilated cardiomyopathy

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