Effects of Statin Withdrawal on Pro-Atherogenic Chemokines

Grant Winners

Dean

Abstract

Statins are the drugs of choice to lower LDL-cholesterol levels and are effective in primary and secondary prevention of atherosclerotic cardiovascular disease. However, discontinuation of statins is associated with a "rebound" increase in cardiovascular events. We propose that a rebound inflammatory response may mediate the adverse effects of statin withdrawal. Our proposal is supported by recent findings indicating that in vascular smooth muscle (VSMC) acute statin withdrawal produce a rebound increase of the effects of angiotensin II, a well-known vasoconstrictor, pro-inflammatory, pro-atherogenic substance, and of the mRNA levels of several leukocyte attractant chemokines Ccl2 (Chemokine, C-C motif, ligand 2); Csf2 (colony stimulating factor 2 - granulocyte-macrophage); Cxcl1 (chemokine - C-X-C motif - ligand 1); and Cxcl2 (chemokine - C-X-C motif - ligand 2). In contrast, statin treatment was without effect. The latter was expected since statins were added to cells lacking pro-inflammatory stimulation. Therefore, in this proposal we would like to determine the effects of statin treatment and withdrawal in VSMC challenged with oxidized LDL-C. To achieve this objective, the following specific aims are proposed: 1) To determine the optimal experimental conditions to observe increased mRNA levels and protein concentrations of leukocyte attractant cytokines (chemokines) induced by oxidized LDL-C; 2) To determine the concentration and time-course effects of statins (simvastatin, lovastatin and atorvastatin) treatment and withdrawal on oxidized LDL-C-induced increase in chemokines; and 3) To determine if changes in mRNA levels are associated with comparable changes in the respective protein levels. We propose that when pro-inflammatory activity is present, statin treatment inhibits, and statin withdrawal will be associated with large rebound increases in the expression and levels of chemokines. Completion of these experiments will provide clues to the mechanisms by which statin withdrawal leads to increase in cardiovascular events.