Rebound Upregulation of Inflammatory Cytokines After Statin Withdrawal

Objective. The development of atherosclerosis relies heavily on production of inflammatory cytokines, therefore we investigated whether statin treatment withdrawal leads to upregulation of cytokines. Background. Cardiovascular disease is the leading cause of death in the US. The HMG-CoA reductase inhibitors (statins) are indicated in the prevention of cardiovascular morbidity and mortality due to atherosclerosis. However, discontinuation of statin treatment induces a rebound dysfunction associated with cardiovascular events. The mechanism underlying these events is unknown and there are no treatment strategies available. Methods. Vascular Smooth Muscle Cells (VSMCs) from Sprague-Dawley rats were cultured in vitro. The VSMCs were treated with simvastatin (1uM or 3uM) for 24h with or without TNF-alpha (5 ng/ml), followed by statin withdrawal (WD). Supernatants of cultures were analyzed for cytokines. Results. VSMC withdrawal of simvastatin without TNF-alpha, increased the CXCL1 by 30% (+/- 2%) and 43% (+/- 2.5%) after 6h and 10h WD respectively. The levels of other pro-atherogenic cytokines examined did not differ significantly from control. WD of VSMCs treated with simvastatin (3uM) and TNF-alpha induced significant increased the protein levels of: (a) CXCL1 by 960% (+/- 300%); (b) CCL2/MCP1 by 300% (+/- 20%); and (c) RANTES by ~400% (+/- 80). Conclusion. Our data suggest that VSMC response to simvastatin treatment and withdrawal may be influenced by a patient’s previous exposure to inflammatory factors. The data support observations that patients with existing cardiovascular dysfunction are at greater risk of adverse rebound effects due to statin withdrawal. Grants. NSU President’s Faculty Research and Development Grant 2008-09.