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Updated: May 1, 2026
A Microphysiological System to Study Leukocyte-Endothelial Cell Interaction during Inflammation
Published on: December 9, 2021
Synergistic therapeutic vascular cytoprotection against complement-mediated injury induced via a PKCα-, AMPK-, and
Shahir S Hamdulay1, Bufei Wang, Damien Calay
1Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, W12 ONN, United Kingdom;
Insights
Rapamycin and atorvastatin synergize to protect against arterial disease by increasing decay-accelerating factor (DAF) on endothelial cells. This pathway offers a potential therapeutic strategy for antibody-mediated vascular conditions.
Area of Science:
- Immunology
- Cardiovascular Biology
- Pharmacology
Background:
- Endothelial injury and dysfunction are key in accelerated arterial disease, including allograft vasculopathy and systemic autoimmune diseases.
- Pathogenic antibodies and complement activation play critical roles in these conditions.
- Rapamycin has shown promise in reducing posttransplant vasculopathy, often used with statins.
Purpose of the Study:
- To investigate the synergistic vasculoprotective mechanisms of rapamycin and atorvastatin.
- To elucidate the molecular pathway involved in their combined therapeutic effect.
- To assess the induction of decay-accelerating factor (DAF) and its role in protection.
Main Methods:
- Experiments were conducted using human endothelial cells and murine models.
- Investigated the activation of protein kinase Cα, AMP-activated kinase, and CREB pathways.
- Analyzed DAF promoter activity, cell surface DAF expression, and protection against complement-mediated injury.
Main Results:
- Rapamycin and atorvastatin demonstrated synergy in human endothelial cells, activating a vasculoprotective pathway.
- This synergy led to increased endothelial DAF expression and enhanced protection against complement-mediated injury.
- In vivo studies confirmed that combined atorvastatin and rapamycin therapy induced DAF on murine aortic endothelium.
Conclusions:
- A rapamycin-atorvastatin synergistic pathway induces endothelial DAF, offering protection against complement-mediated injury.
- This mechanism is therapeutically relevant for antibody-mediated vascular diseases like posttransplant vasculopathy and systemic lupus erythematosus.
- The findings suggest a broadly applicable vasculoprotective strategy targeting DAF induction.
Abstract:
Endothelial injury and dysfunction precede accelerated arterial disease in allograft vasculopathy and systemic autoimmune diseases and involve pathogenic Abs and complement. Recent reports suggest that switching to rapamycin from calcineurin antagonists reduces posttransplant vasculopathy and prolongs survival following cardiac transplantion. The majority of these patients also receive statin therapy. We examined potential mechanisms underlying this protective response in human endothelial cells and identified synergy between rapamycin and atorvastatin. Mechanistically, atorvastatin and rapamycin activated a protein kinase Cα, AMP-activated kinase, and CREB-dependent vasculoprotective pathway, which induced decay-accelerating factor (DAF) promoter activity via binding to the cAMP response element, mutation of which attenuated promoter activity. This response significantly increased endothelial cell surface DAF and enhanced protection against complement-mediated injury. Synergy with rapamycin was reproduced by simvastatin, whereas combining atorvastatin with cyclosporine or mycophenolate in place of rapamycin was ineffective. Importantly, synergy was reproduced in vivo, in which only atorvastatin and rapamycin therapy in combination was sufficient to induce DAF on murine aortic endothelium. We believe this pathway represents an important therapeutically inducible vasculoprotective mechanism for diseases mediated by pathogenic Abs and complement, including posttransplant vasculopathy and systemic lupus erythematosus. Although our study focuses on the vascular endothelium, the findings are likely to be broadly applicable, given the diverse cellular expression of DAF.
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