Anti-atherosclerotic potential of dihydropyridine calcium channel blockers

Dihydropyridine calcium channel blockers (CCBs) are widely used agents for patients with hypertension. Dihydropyridine CCBs lower blood pressure mainly through vasodilation and reduction of peripheral resistance, and several clinical studies have demonstrated that they have clinical benefits in patients with cardiovascular diseases. In addition, some studies have indicated that dihydropyridine CCBs have anti-atherogenic effects beyond their blood pressure-lowering effects. In fact, several studies using atherosclerotic model animals have revealed that dihydropyridine CCBs suppress atherosclerotic lesion formation. It is well known that the production of reactive oxygen species (ROS) is involved in the progression of atherosclerosis by stimulating the production of inflammatory factors such as chemokines, cytokines and adhesion molecules. Dihydropyridine CCBs can suppress ROS generation and subsequent inflammatory actions in vascular cells and arterial walls. Furthermore, several reports have revealed that dihydropyridine CCBs suppress the expression of adhesion molecules, thereby inhibiting monocyte adhesion to endothelial cells, which is thought to be an early step in the pathogenesis of atherosclerosis. In smooth muscle cells, dihydropyridine CCBs suppress cell proliferation and migration in vitro and in vivo. In macrophages, dihydropyridine CCBs decrease cholesterol accumulation and intracellular cholesterol esterification, and increase cholesteryl ester hydrolysis. Moreover, dihydropyridine CCBs suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. Interestingly, recent studies have revealed that the anti-atherosclerotic effects of dihydropyridine CCBs are mediated, at least in part, via the activation of peroxisome proliferator-activated receptor-γ. In this review, we focus on the anti-atherosclerotic effects of dihydropyridine CCBs beyond their blood pressure-lowering effects.