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Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated
Justin C Mason1, Zahra Ahmed, Rivka Mankoff
1British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College, Hammersmith Hospital, London, UK. justin.mason@ic.ac.uk
Insights
Statins enhance endothelial cell protection against complement-mediated injury by increasing decay-accelerating factor (DAF) expression, independent of lipid-lowering effects. This cytoprotective action may reduce atherosclerosis and myocardial infarction risks.
Area of Science:
- Cardiovascular Biology
- Immunology
- Pharmacology
Background:
- Complement-mediated vascular injury contributes to atherosclerosis and myocardial infarction.
- Statins offer endothelial cell (EC) benefits beyond lipid reduction.
- The mechanism of statin-induced EC protection against complement is unclear.
Purpose of the Study:
- To investigate if statins upregulate complement-inhibitory proteins on vascular ECs.
- To explore the molecular pathways involved in statin-mediated EC protection.
- To determine the functional consequences of statin-induced changes in ECs.
Main Methods:
- Human umbilical vein and aortic ECs treated with atorvastatin or simvastatin.
- Flow cytometry used to measure decay-accelerating factor (DAF), membrane cofactor protein, and CD59 expression.
- Analysis of mRNA, protein synthesis, and signaling pathways (PKCα, RhoA, PI3K).
Main Results:
- Statins significantly increased DAF expression (up to 4-fold) in a dose-dependent manner.
- Statin-induced DAF upregulation requires de novo protein synthesis and is linked to HMG-CoA reductase inhibition.
- Increased DAF expression functionally reduced complement component C3 deposition and EC lysis.
Conclusions:
- Statins provide a novel cytoprotective effect on vascular endothelium independent of lipid lowering.
- Upregulation of DAF enhances EC resistance to complement-mediated injury.
- Modulation of complement regulatory proteins may contribute to statins' early benefits in cardiovascular disease.
Abstract:
Complement-mediated vascular injury is important in the pathophysiology of atherosclerosis and myocardial infarction. Because recent evidence shows that statins have beneficial effects on endothelial cell (EC) function independent of lipid lowering, we explored the hypothesis that statins modulate vascular EC resistance to complement through the upregulation of complement-inhibitory proteins. Human umbilical vein and aortic ECs were treated with atorvastatin or simvastatin, and decay-accelerating factor (DAF), membrane cofactor protein, and CD59 expression was measured by flow cytometry. A dose-dependent increase in DAF expression of up to 4-fold was seen 24 to 48 hours after treatment. Statin-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. L-Mevalonate and geranylgeranyl pyrophosphate reversed the effect, confirming the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition and suggesting that constitutive DAF expression is negatively regulated by geranylgeranylation. Neither farnesyl pyrophosphate nor squalene inhibited statin-induced DAF expression, suggesting that the effect is independent of cholesterol lowering. Statin-induced DAF upregulation was mediated by the activation of protein kinase Calpha and inhibition of RhoA and was independent of phosphatidylinositol-3 kinase and NO activity. The increased DAF expression was functionally effective, resulting in significant reduction of C3 deposition and complement-mediated lysis of antibody-coated ECs. These observations provide evidence for a novel cytoprotective action of statins on vascular endothelium that is independent of the effect on lipids and results in enhanced protection against complement-mediated injury. Modulation of complement regulatory protein expression may contribute to the early beneficial effects of statins in reducing the morbidity and mortality associated with atherosclerosis.