L-type calcium channel inhibitor diltiazem prevents aneurysm formation by blood pressure-independent anti-inflammatory effects

Formation of abdominal aortic aneurysms is a progressive inflammatory process that involves infiltration and differentiation of monocytes in the vessel wall, proliferation and migration of smooth muscle cells, and eventually the degradation of the internal elastic lamina, which leads to outward vascular remodeling and distension of the vessel. Because Calcium Channel blockers exert multiple beneficial effects on the vascular system, we investigated the effect of the benzothiazepine-type Calcium Channel blocker diltiazem on aneurysm formation in a mouse model. Angiotensin II infusion induced massive suprarenal aortic aneurysm formation in male Apolipoprotein E-deficient mice that was blocked by cotreatment with diltiazem even if the blood pressure was controlled by coinfusion of phenylephrine. Diltiazem prevented the angiotensin II-mediated induction of proinflammatory cytokines after 7 days of angiotensin II treatment in the aortic arch attributable to a reduction in the amount of locally infiltrating macrophages. To identify the underlying mechanism, vascular segments and cultured vascular cells as well as monocytes were studied. Diltiazem failed to reduce the angiotensin II-induced expression of proinflammatory chemokines and cytokines in isolated mouse thoracic aortic segments in organ culture. Furthermore, diltiazem did not affect the recruitment of proinflammatory Ly6C(+) monocytes in vivo pointing toward an effect of the compound on gene expression in monocytes/macrophages. Indeed, diltiazem prevented the interleukin-6-induced mRNA expression of interleukin-1β and the monocyte chemoattractant protein CCL12 in peritoneal macrophages and RAW264.7 cells independent of the intracellular calcium concentration. Thus, diltiazem limits aortic aneurysm formation in mice by a blood pressure-independent anti-inflammatory effect on monocytic cells.