Abstract 5514: Aliskiren, a Direct Renin Inhibitor, Prevents Leukocyte Recruitment to Mouse Femoral Artery via Blood Pressure-Independent Modulation of Adhesion Molecules and Oxidative Stress
[Background] Renin-angiotensin system (RAS) plays a central role in the atherosclerosis and its inhibition has beneficial effects in atherogenesis. Recent observation with aliskiren, a direct renin inhibitor, demonstrated its protective effects in atherosclerosis-prone mice. However, patholphysiological consequence of renin inhibition in vascular inflammation has not been studied.
[Aim] To investigate an effect of aliskiren on vascular inflammation, we conducted leukocyte adhesion assay in vivo using a novel real-time imaging system. Further, we examined an effect of aliskiren in leukocyte endothelial interaction in vitro to dissect its molecular background.
[Methods and results] Aliskiren (10mg/kg/day n=6) or PBS (n=7) was continuously administered to male BL6 mouse for 2 weeks via osmotic pump. Blood pressure of the animals were not significantly changed in two groups throughout experimental period. A perivascular cuff injury was then introduced to the femoral artery and a real time intravital microscopic imaging was conducted 24 hours after injury. The number of adherent leukocyte was elevated in the PBS group (43.8 ± 9.3/10−2 mm2) which was significantly reduced in the aliskiren group (18.4 ± 4.4, p<0.05). We then examined the effect of aliskiren in leukocyte-endothelial interaction in vitro under flow. Treatment of human umbilical vein endothelial cells (HUVEC) with aliskiren (10−6 M, 4 hours) significantly reduced adhesion of THP-1 cells to activated HUVEC (TNFα, 6.6 ±1.3/HPF; TNF α + aliskiren, 2.2 ± 0.6/HPF; p<0.05). A real time PCR analysis revealed that the expression levels of ICAM and VCAM in HUVEC were reduced after aliskiren treatment. Further, activation of JNK and ERK and production of reactive oxygen species were abolished in HUVEC after aliskiren treatment.
[Conclusions] Renin inhibition modulated leukocyte recruitment to the vascular injury in vivo and in vitro independent from its effect on blood pressure, suggesting a novel anti-inflammatory role for this compound.