l -Type Calcium Channel Inhibitor Diltiazem Prevents Aneurysm Formation by Blood Pressure–Independent Anti-Inflammatory Effects

Abstract

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.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…L-type Ca 2ϩ channel also plays a role in ANG II-induced AAA development. Diltiazem prevents AAA and aortic inflammation in apoEϪ/Ϫ mice with ANG II infusion, and this effect appears independent of blood pressure (696). L-type Ca 2ϩ channel inhibitor, nifedipine, reduces AAA incidence, attenuates superoxide production, and recouples eNOS, which points to a ROS-dependent mechanism of AAA formation in this mouse model (695).…”

IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice

“…Accordingly, in vitro treatment with the L-type calcium channel blocker diltiazem blunts the differentiation of CD4+ cells into Th17 cells (Li et al, 2012). We fed mice with or without diltiazem in their drinking water (Mieth et al, 2013; Semsarian et al, 2002) and infused them with vehicle or cPTH. Diltiazem blocked the increase in the number of BM Th17 cells (fig.6a), the BM mRNA levels of IL-17A (fig.6b), and the BM CD4+ cell expression of RORα and RORγt (fig.6c,d) induced by cPTH.…”

Nifedipine attenuation of abdominal aortic aneurysm in hypertensive and non-hypertensive mice: Mechanisms and implications

“…However, in other studies Amlodipine [7], or in combination with Atorvastatin [37], was found effective in preventing AAA in experimental mice. Several other CCBs, such as Diltiazem [8] and Azelnidipine [9], were also found to prevent AAA in mice. Nifedipine has been shown to inhibit AAA formation in a rat model through a NF-κB and MMP-9 dependent manner [12].…”

“…While different CCBs have different potencies and pharmacokinetics, they all reduce blood pressure via vasodilation from the blockade of calcium channels in vascular smooth muscle. Some previous studies have shown that CCBs may be effective in the prevention of AAA [7, 8, 12], while others found the opposite [13–15]. Further, these studies did not dissect out an anti-hypertensive effect of CCBs as a potential cause of AAA protection.…”