Abstract
BackgroundGiven the complex nature of cardiovascular disease (CVD), information derived from a systems-level will allow us to fully interrogate features of CVD to better understand disease pathogenesis and to identify new drug targets.ResultsHere, we describe a systematic assessment of the multi-layer interactions underlying cardiovascular drugs, targets, genes and disorders to reveal comprehensive insights into cardiovascular systems biology and pharmacology. We have identified 206 effect-mediating drug targets, which are modulated by 254 unique drugs, of which, 43% display activities across different protein families (sequence similarity < 30%), highlighting the fact that multitarget therapy is suitable for CVD. Although there is little overlap between cardiovascular protein targets and disease genes, the two groups have similar pleiotropy and intimate relationships in the human disease gene-gene and cellular networks, supporting their similar characteristics in disease development and response to therapy. We also characterize the relationships between different cardiovascular disorders, which reveal that they share more etiological commonalities with each other rooted in the global disease-disease networks. Furthermore, the disease modular analysis demonstrates apparent molecular connection between 227 cardiovascular disease pairs.ConclusionsAll these provide important consensus as to the cause, prevention, and treatment of various CVD disorders from systems-level perspective.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-014-0141-z) contains supplementary material, which is available to authorized users.
Highlights
Given the complex nature of cardiovascular disease (CVD), information derived from a systems-level will allow us to fully interrogate features of CVD to better understand disease pathogenesis and to identify new drug targets
Classification of cardiovascular drugs and their therapeutic targets The careful curation of the drug-target data set involves the identification of approved cardiovascular drugs with successful cardiovascular protein targets
This results in a list of 254 drugs that act on 206 protein targets (Additional file 1)
Summary
Given the complex nature of cardiovascular disease (CVD), information derived from a systems-level will allow us to fully interrogate features of CVD to better understand disease pathogenesis and to identify new drug targets. The prospect for the cardiovascular disease (CVD) pharmacotherapy seems to have ‘hit the wall’, with multiple high-profile trial failures and declining industrial interest. Reasons for such predicament might include an intensive regulatory environment, a competitive market, the elevated bar of existing medicines for further innovation and the increasing cost of mega-trials. It is appreciated that many drugs with a specific efficacy act on multiple protein targets [10,11]. This so-called polypharmacology is an undesirable property in the conventional reductionist paradigm and might be more suitable to view through the lens of systemsbased approaches [11]
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