Combination of amlodipine and atorvastatin synergistically reduces leukocyte recruitment to mechanically injured mouse femoral artery

Hagita, Sumihiko; Osaka, Mizuko; Shimokado, Kentaro; Yoshida, Masayuki

doi:10.1038/hr.2010.254

Cited by 4 publications

(4 citation statements)

References 27 publications

(40 reference statements)

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“…To determine the physiological role of AhR, we investigated the effect of endothelial cell-specific AhR deficiency on the indoxyl sulfate-enhanced leukocyteendothelial interactions using an IVM system 23,[29][30][31][32][33] . First, we purified endothelial cells from lungs taken from AhR fl/fl and eAhR KO mice to confirm the expression of AhR.…”

Section: Indoxyl Sulfate-enhanced Leukocyte -Endothelialmentioning

confidence: 99%

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Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

Ito

Osaka

Edamatsu

et al. 2016

JAT

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Aim:The aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor mediating toxic effects of dioxins and uremic toxins, has recently emerged as a pathophysiological regulator of immune-inflammatory conditions. Indoxyl sulfate, a uremic toxin, is associated with cardiovascular disease in patients with chronic kidney disease and has been shown to be a ligand for AhR. The aim of this study was to investigate the potential role of AhR in indoxyl sulfate-induced leukocyte -endothelial interactions. Methods: Endothelial cell-specific AhR knockout (eAhR KO) mice were produced by crossing AhR floxed mice with Tie2 Cre mice. Indoxyl sulfate was administered for 2 weeks, followed by injection of TNF-. Leukocyte recruitment to the femoral artery was assessed by intravital microscopy. Vascular endothelial cells were transfected with siRNA specific to AhR (siAhR) and treated with indoxyl sulfate, followed by stimulation with TNF-. Results: Indoxyl sulfate dramatically enhanced TNF--induced leukocyte recruitment to the vascular wall in control animals but not in eAhR KO mice. In endothelial cells, siAhR significantly reduced indoxyl sulfate-enhanced leukocyte adhesion as well as E-selectin expression, whereas the activation of JNK and nuclear factor-B was not affected. A luciferase assay revealed that the region between 153 and 146 bps in the E-selectin promoter was responsible for indoxyl sulfate activity via AhR. Mutational analysis of this region revealed that activator protein-1 (AP-1) is responsible for indoxyl sulfate-triggered E-selectin expression via AhR. Conclusion: AhR mediates indoxyl sulfate-enhanced leukocyte -endothelial interactions through AP-1 transcriptional activity, which may constitute a new mechanism of vascular inflammation in patients with renal disease.

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Section: Indoxyl Sulfate-enhanced Leukocyte -Endothelialmentioning

confidence: 99%

“…Leukocyte adhesion in the femoral artery was assessed 3 h after this treatment by intravital microscopy (IVM) as previously described 23,[29][30][31][32][33] . In brief, mice were injected via the left femoral vein with rhodamine 6G chloride (Molecular Probes, Eugene, OR) to label leukocytes in vivo.…”

Section: Detection Of Reactive Oxygen Species (Ros)mentioning

confidence: 99%

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

Ito

Osaka

Edamatsu

et al. 2016

JAT

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“…In a mouse model of femoral artery injury, the combination therapy attenuated leukocyte adhesion and oxidative stress [34]. In a rat ischemic stroke model, pretreatment with atorvastatin and amlodipine ameliorated post-ischemic brain weight increase and induction of MMP-9 [35].…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

et al. 2013

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BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.Methods and ResultsExperimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.ConclusionsRho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.

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“…In this issue of Hypertension Research, Hagita et al elegantly demonstrated a potential synergistic effect of the combination of a calcium channel blocker and a statin on the vascular inflammation after mechanical vascular injury in vivo. 8 In this study, the authors evaluated the effects of a combination of a calcium channel blocker (amlodipine) and a statin (atorvastatin) by focusing on their effects on leukocyte recruitment to the vasculature. The authors recently developed a novel intravital microscopic system to directly monitor leukocyte recruitment in atheroprone arteries in vivo by taking advantage of the mouse model of endovascular injury developed by Sata et al 9 This injury resembles balloon angioplasty, which is characterized by complete endothelial denudation and acute onset of medial smooth muscle cell apoptosis followed by reproducible neointima formation.…”

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confidence: 99%

Synergistic protection against vascular inflammation with a calcium channel blocker and a statin

Hirata

Sata

2011

Hypertens Res

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C ardiovascular disease (CVD) is a leading cause of death worldwide. As CVD drives high healthcare costs in surviving events such as stroke and heart failure, better strategies to facilitate to prevent CVD have become priorities for most healthcare systems. Modification of cardiovascular risk factors is essential to reduce incidence of CVD. Cardiovascular risk factors are highly interactive and thereby contribute synergistically to the pathogenesis of atherosclerotic diseases. 1 Epidemiologic studies revealed that hypertension usually occurs in conjunction with other metabolically linked risk factors; such as glucose intolerance, obesity, left ventricular hypertrophy and dislipidemia. 2 Cowie estimated that over half of the hypertensive population also has dyslipidemia. 3 It has also become clear that CVD risk factors tend to increase the total or absolute CVD risk in a multiplicative rather than additive manner. 4 Thus, individual treatment strategies should be based on absolute cardiovascular risk, which could be determined by the synergistic effect of all cardiovascular risk factors rather than on individual risk factors. 5 To effectively reduce CVD risk in hypertensive patients at high cardiovascular risk, concomitant lipid-lowering therapy with HMG-CoA reductase inhibitors, stains, would be necessary as well as rigorous blood pressure control with two or more antihypertensive agents. These recommendations concur with the results of large clinical trials that demonstrated clinical benefit of statin therapy in hypertensive patients with normal lipid levels. 6 The antihypertensive efficacy of amlodipine and the lipid-lowering efficacy of atorvastatin are well established. The efficacy of the combined administration of amlodipine and atorvastatin in reducing coronary risk factors and cardiovascular morbidity has been evaluated in adult patients in several trials. Two randomized, double-blind, double-dummy, multicenter trials (AVALON, RESPOND) compared the efficacy of the coadministration of amlodipine and atorvastatin with that of single-agent therapy or placebo over 8 weeks. Five non-comparative, titration-to-goal, multicenter studies (GEMINI, GEMINI-ALAA, JEWEL I, JEWEL II, CAPABLE) evaluated the efficacy of the fixed-dose combination amlodipine/ atorvastatin in a clinical-practice setting over 14, 16 and 20 weeks.A 2Â2 factorial analysis of the data from the randomized, double-blind, multicenter trial evaluated the efficacy of amlodipine plus atorvastatin over 3.3 years (ASCOT-LLA). The randomized ASCOTT-LLA included patients with a total cholesterol concentration p250 mg dl À1 who were already enrolled in ASCOT-BPLA. 6 ASCOT-BPLA was a large, multicenter trial that used a PROBE (prospective, randomized, open-label and blinded endpoint) evaluation design to compare amlodipine-based with atenololbased therapy in hypertensive patients. 7 Patients eligible for ASCOT-LLA were further randomized to receive atorvastatin or placebo in addition to the blood pressure lowering medication in a double-blind manner. A pr...

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Combination of amlodipine and atorvastatin synergistically reduces leukocyte recruitment to mechanically injured mouse femoral artery

Cited by 4 publications

References 27 publications

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

Synergistic protection against vascular inflammation with a calcium channel blocker and a statin

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