A systems biology and proteomics-based approach identifies SRC and VEGFA as biomarkers in risk factor mediated coronary heart disease

Abstract

Coronary heart disease (CHD) is the most common cause of death worldwide. The burden of CHD increases with risk factors such as smoking, hypertension, obesity and diabetes. Several studies have demonstrated the association of these classical risk factors with CHD. However, the mechanisms of these associations remain largely unclear due to the complexity of disease pathophysiology and the lack of an integrative approach that fails to provide a definite understanding of molecular linkage. To overcome these problems, we propose a novel systems biology approach that relates causative genes, interactomes and pathways to elucidate the risk factors mediating the molecular mechanisms and biomarkers for feasible diagnosis. The literature was mined to retrieve the causative genes of each risk factor and CHD to construct protein interactomes. The interactomes were examined to identify 298 common molecular signatures. The common signatures were mapped to the tissue network to synthesize a sub-network consisting of 82 proteins. Further, the dissection of the sub-network provides functional modules representing a diverse range of molecular functions, including the AKT/p13k, MAPK and wnt pathways. Also, the prioritization of functional modules identifies SRC, VEGFA and HIF1A as potential candidate markers. Further, we validate these candidates with the existing markers CRP, NOS3 and VCAM1 in the serum of 63 individuals, 33 with CHD and 30 controls, using ELISA. SRC, VEGFA, H1F1A, CRP and NOS3 were significantly altered in patients compared to controls. These results support the utility of these candidate markers for the diagnosis of CHD. Overall, our molecular observations indicate the influence of risk factors in the pathophysiology of CHD and identify serum markers for diagnosis.

Integrative gene ontology and network analysis of coronary artery disease associated genes suggests potential role of ErbB pathway gene EGFR

“…It is considered to be a focal adhesion molecule and has been demonstrated to regulate vasoconstriction ( 50 ). Higher serum levels of Src have been detected in CAD subjects ( 51 ). AKT serine/threonine kinase 1 (Akt1) acts downstream to the Src and its active form are highly abundant in heart tissue, endothelial cells, platelets and SMC ( 52 – 54 ).…”

Proteomic Studies of Blood and Vascular Wall in Atherosclerosis

“…Using proteomic analysis, 298 proteins associated with the pathogenesis of coronary atherosclerosis were specifically studied in 63 people (33 with coronary heart disease and 30 in the control group). 82 differentially expressed proteins were identified that distinguish coronary atherosclerosis, including C-reactive protein, vascular endothelial growth factor, NO synthase and adhesive molecules of vascular endothelium type 1 [14].…”