Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

Area of Science:

• Proteomics
• Drug Discovery
• Cardiovascular Biology

Background:

• Cardiovascular disease (CVD) remains a leading global cause of mortality, with a significant unmet need for novel therapeutic agents.
• Understanding the molecular underpinnings of CVD progression is crucial for identifying effective drug candidates.
• Current therapeutic strategies often lack the ability to reverse advanced disease pathology.

Purpose of the Study:

• To identify potential drug candidates capable of reversing the proteomic signature of advanced cardiovascular disease (CVD).
• To investigate the role of specific proteins, such as cytosolic phospholipase A2 (cPLA2), in CVD progression.
• To evaluate the therapeutic efficacy of a predicted drug candidate in preclinical models of vascular calcification.

Main Methods:

• Comparative proteomic analysis of arterial tissue from early-stage versus advanced-stage CVD patients.
• In silico prediction of small bioactive molecules to reverse identified CVD-associated proteomic changes.
• In vivo evaluation of the top-predicted drug candidate (AACOCF3) in a cholecalciferol-induced vascular calcification mouse model.
• In vitro assessment of AACOCF3's effect on osteoinductive signaling in human aortic smooth muscle cells.

Main Results:

• Approximately 4000 proteins were identified, with 100 upregulated and 52 downregulated in advanced CVD.
• Arachidonyl trifluoromethyl ketone (AACOCF3), a cPLA2 inhibitor, was predicted as the most effective compound to reverse the advanced CVD proteomic signature.
• Vascular cPLA2 expression was elevated in advanced CVD patients.
• AACOCF3 treatment significantly reduced vascular calcification in vivo and inhibited osteoinductive signaling in vitro and in vivo.

Conclusions:

• A systems biology approach successfully identified a novel compound (AACOCF3) with potential to prevent vascular calcification in CVD.
• Inhibition of cPLA2 represents a promising therapeutic strategy for mitigating vascular calcification.
• This drug discovery strategy holds potential for identifying novel candidates for other complex diseases beyond CVD.