Network determinants of cardiovascular calcification and repositioned drug treatments

Area of Science:

• Cardiovascular Biology
• Network Pharmacology
• Drug Discovery

Background:

• Ectopic cardiovascular calcification is a prevalent condition lacking effective treatments.
• Current therapeutic options for vascular calcification are limited.
• Novel strategies are needed to prevent or treat cardiovascular calcification progression.

Purpose of the Study:

• To identify a molecular network module associated with human vascular calcification.
• To discover novel drug candidates for repurposing to treat cardiovascular calcification.
• To validate the efficacy of predicted drugs in an in vitro calcification model.

Main Methods:

• Construction of a human calcification endophenotype module (calcificasome) using protein-protein interaction networks.
• Network proximity analysis to identify overlaps with inflammation, thrombosis, and fibrosis modules.
• Network-based drug repurposing analysis to predict candidate therapeutics.
• In vitro validation of drug efficacy using human coronary artery smooth muscle cells.

Main Results:

• The calcificasome module significantly overlapped with inflammation, thrombosis, and fibrosis networks.
• Everolimus, temsirolimus, and pomalidomide were predicted to target the calcificasome.
• These drugs significantly reduced in vitro calcification in human coronary artery smooth muscle cells.
• Drugs modulated their predicted network targets, confirming mechanism of action.

Conclusions:

• An integrated network approach successfully identified novel mediators of ectopic cardiovascular calcification.
• Everolimus, temsirolimus, and pomalidomide show promise as repurposed drugs for cardiovascular calcification.
• The developed methodological framework is applicable to drug repurposing for other diseases.