Abstract
Background: Coronary artery disease (CAD) exerts a global challenge to public health. Genetic heritability is one of the most vital contributing factors in the pathophysiology of CAD. Co-expression network analysis is an applicable and robust method for the interpretation of biological interaction from microarray data. Previous CAD studies have focused on peripheral blood samples since the processes of CAD may vary from tissue to blood. It is therefore necessary to find biomarkers for CAD in heart tissues; their association also requires further illustration. Materials and Methods: To filter for causal genes, an analysis of microarray expression profiles, GSE12504 and GSE22253, was performed with weighted gene co-expression network analysis (WGCNA). Co-expression modules were constructed after batch effect removal and data normalization. The results showed that 7 co-expression modules with 8,525 genes and 1,210 differentially expressed genes (DEGs) were identified. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Four major pathways in CAD tissue and hub genes were addressed in the Hybrid Mouse Diversity Panel (HMDP) and Human Protein Atlas (HPA), and isoproterenol (ISO)/doxycycline (DOX)-induced heart toxicity models were used to validate the hub genes. Lastly, the hub genes and risk variants were verified in the CAD cohort and in genome-wide association studies (GWAS). Results: The results showed that RNF181 and eight other hub genes are perturbed during CAD in heart tissues. Additionally, the expression of RNF181 was validated using RT-PCR and immunohistochemistry (IHC) staining in two cardiotoxicity mouse models. The association was further verified in the CAD patient cohort and in GWAS. Conclusion: Our findings illustrated for the first time that the E3 ubiquitination ligase protein RNF181 may serve as a potential biomarker in CAD, but further in vivo validation is warranted.
Highlights
Coronary artery disease (CAD) has been noted as a challenge to public health faced by most industrialized and developing countries (Naghavi et al, 2017)
Our results revealed for the first time that RNF181 may be a causal gene for CAD, possibly through decreasing the degradation of VEGF2 mediated by the NEDD4 and ERK/MAPK signaling pathways
We focused on the hub genes and the risk factors for CAD in heart tissue with in-depth insight
Summary
Coronary artery disease (CAD) has been noted as a challenge to public health faced by most industrialized and developing countries (Naghavi et al, 2017). CAD is a progressive cardiovascular disease that develops following atherosclerotic plaque formation or atherosclerotic occlusion of major arteries in the heart (Fuster et al, 1992) In this pathological process, fatty acid metabolism, glucose oxidation, mitochondrial fission, and oxidative stress largely impact the prognosis of the disease. Strategic treatments in clinical practice include carnitine palmitoyltransferase-1 (CPT-1) inhibitors (etomoxir, oxfenicine, etc.), malonyl-CoA inhibitors (trimetazidine), β-blockers, anti-ischemic agents, and the novel mitochondrial dynamic modulators, such as the Drp inhibitor These drugs have various disadvantages: inhibition of CPT-1 causes lipotoxicity in the pathological heart, leading to cardiac exacerbation; malonyl CoA inhibitor impedes the synthesis of fatty acid, but causes neuronal and cognition side effects to the brain; Drp is able to inhibit mitochondrial fission under oxidative stress conditions—its long-term effectiveness and safety remain to be discussed. It is necessary to find biomarkers for CAD in heart tissues; their association requires further illustration
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