Dynamic Observation of Mechanically-Injured Mouse Femoral Artery Reveals an Antiinflammatory Effect of Renin Inhibitor

Abstract

Objective-The renin-angiotensin-aldosterone system (RAS) plays a central role in atherosclerosis. To investigate the effects of a direct renin inhibitor aliskiren on vascular inflammation, we conducted leukocyte adhesion assays in vivo and in vitro using a novel real-time imaging system. Methods and Results-Aliskiren (10 mg/kg/d) or PBS was administered to C57BL/6 mice (6 -7 weeks of age; Oriental Yeast, Tokyo, Japan) for 2 weeks via an osmotic pump. Blood pressure was not significantly changed in the 2 groups throughout the experimental period. A perivascular cuff injury was then introduced to the femoral artery and real-time intravital microscopic observation was conducted 24 hours after injury. The number of adherent leukocytes was elevated in the injured mice without aliskiren (43.8Ϯ9.3/10 Ϫ2 mm 2 ), whereas that was significantly reduced in the mice with aliskiren (18. 4Ϯ4.4, PϽ0.05). Treatment of human umbilical vein endothelial cells (HUVECs) with aliskiren significantly reduced the adhesion of THP-1 cells to TNF-␣-activated HUVECs (PϽ0.05). Interestingly, TNF-␣-induced renin activity and angiotensin II production in HUVECs were also blunted by aliskiren. Furthermore, exogenous renin and angiotensin II abrogated the aliskiren-mediated reduction of THP-1 cell adhesion to HUVECs. Key Words: atherosclerosis Ⅲ renin-angiotensin-aldosterone system Ⅲ renin inhibition Ⅲ endothelium T he renin-angiotensin-aldosterone system (RAS) has been recognized as one of the key mechanisms involved in various vascular diseases including atherosclerosis. [1][2][3] Recent reports have also demonstrated that production of RAS in extrarenal tissues exerts critical biological effects, 4 -7 whereas regulation of local RAS contributes to the pathophysiological condition of endothelial cells and smooth muscle cells. 8,9 Therefore, modulation of local as well as systemic RAS has emerged as a therapeutic concept for cardiovascular diseases. Conclusions-OurAngiotensin (Ang) II, a potent vasoconstrictive peptide, plays a crucial role in atherosclerosis via local activation of mitogen-activated protein kinases (MAPK). In addition, we previously found that Ang II-related oxidative stress in leukocytes induces leukocyte recruitment in vivo. 10 However, the continued presence of other bioactive angiotensin-related peptides has made it difficult to elucidate the contributions of Ang II in these processes.Renin, a rate-limiting enzyme for Ang II formation, exerts various inflammatory reactions, including activation of thrombogenic molecules 11 and intracellular signaling proteins independent of local Ang II, 12 which are mediated via the recently characterized renin receptor (RR). 13 Recently aliskiren, a direct renin inhibitor, has been shown to modulate vascular diseases such as hypertension, 14 experimental atherosclerosis, 15 and diabetic nephropathy 16 via RAS dependent or independent pathway. Although local RAS are important in those processes, the importance of renin inhibition in vascular inflammation has not been elucidated.In the ...

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

“…In the present study, aliskiren attenuated the intense pro-inflammatory profile in retina of Ren-2 rats with diabetes or OIR, with a reduction in leucostasis, ICAM-1 production and ED-1 immunolabelling to control levels. There is evidence that aliskiren reduced the macrophage content of atherosclerotic plaques [30], leucocyte adhesion in femoral arteries [31] and the number of CD11b + and CD11c + antigen presenting cells in a model of multiple sclerosis [32]. The results of the present study are consistent with these findings, and highlight the potent anti-inflammatory properties of aliskiren.…”

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

“…The anti-inflammatory effect of aliskiren has been supported by many researches, Jun et al, in 2009 demonstrated that renin inhibition by aliskiren significantly reduced the expression of VCAM-1 and ICAM in injured arteries, also he found that the expression of NF-k B, was attenuated by aliskiren [45]. In addition, Alessandra et al, showed that aliskiren down-regulates TNF-α-stimulated TF expression in HUVECs.…”

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

“…The dose of aliskiren was determined according to previous studies. 20,21 Renal artery constriction (RAC) was performed by making dorsal, longitudinal incisions to expose the kidneys. The trunk of the left renal artery, which showed visible renal ischemia, was constricted by a vascular clamp (0.4-1.0 mm; S&T Fine Science Tools, North Vancouver, B.C.…”