A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice

Major, Terry C.; Olszewski, Bronia; Rosebury-Smith, Wendy S.

doi:10.1007/s10557-008-6157-0

Cited by 11 publications

(10 citation statements)

References 42 publications

(49 reference statements)

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“…In addition to the experimental data, clinical studies with patients confirmed the up-regulation of several C-C chemokines in patients with atherosclerosis, unstable angina pectoris, and myocardial infarction (31,32). The important role of C-C chemokines in atherogenesis was further confirmed by broad spectrum C-C chemokine blockers, which inhibited atherosclerotic plaque formation in mice (33,34). The latter studies point to the therapeutic potential of C-C chemokine receptor blockade for atherosclerosis.…”

Section: Discussionmentioning

confidence: 74%

Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis

Alla

Langer

Elzahwy

et al. 2010

Journal of Biological Chemistry

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Many experimental and clinical studies suggest a relationship between enhanced angiotensin II release by the angiotensinconverting enzyme (ACE) and the pathophysiology of atherosclerosis. The atherosclerosis-enhancing effects of angiotensin II are complex and incompletely understood. To identify antiatherogenic target genes, we performed microarray gene expression profiling of the aorta during atherosclerosis prevention with the ACE inhibitor, captopril. Atherosclerosis-prone apolipoprotein E (apoE)-deficient mice were used as a model to decipher susceptible genes regulated during atherosclerosis prevention with captopril. Microarray gene expression profiling and immunohistology revealed that captopril treatment for 7 months strongly decreased the recruitment of pro-atherogenic immune cells into the aorta. Captopril-mediated inhibition of plaque-infiltrating immune cells involved down-regulation of the C-C chemokine receptor 9 (CCR9). Reduced cell migration correlated with decreased numbers of aorta-resident cells expressing the CCR9-specific chemoattractant factor, chemokine ligand 25 (CCL25). The CCL25-CCR9 axis was pro-atherogenic, because inhibition of CCR9 by RNA interference in hematopoietic progenitors of apoE-deficient mice significantly retarded the development of atherosclerosis. Analysis of coronary artery biopsy specimens of patients with coronary artery atherosclerosis undergoing bypass surgery also showed strong infiltrates of CCR9-positive cells in atherosclerotic lesions. Thus, the C-C chemokine receptor, CCR9, exerts a significant role in atherosclerosis.Several clinical studies show that pharmacological inhibition of the renin-angiotensin-aldosterone system could mediate atheroprotection (1-4). In agreement with those clinical data, experimental studies demonstrated a causal relationship between angiotensin II release by the angiotensin-converting enzyme (ACE), 2 the angiotensin II AT 1 receptor, and the development of atherosclerosis because genetic inactivation of either ACE or the AT 1 receptor prevents atherosclerosis development in various animal models of atherosclerosis (5, 6). Likewise, inhibition of angiotensin II activity by ACE inhibitors or AT 1 receptor antagonists is curative in such animal models of atherosclerosis (7,8).In view of the major anti-atherosclerotic effects of ACE inhibitors and AT 1 antagonists, many studies investigated mechanisms that could contribute to atheroprotection upon angiotensin II inhibition. The effects of angiotensin II in atherosclerosis are complex involving actions on circulating blood cells and arterial smooth muscle cells as major targets (9 -11). Established pro-atherogenic effects of angiotensin II on smooth muscle cells are related to a phenotype transformation from contractile to synthetic (11). The effects of angiotensin II on circulating immune cells are less clear, although, gene inactivation studies clearly demonstrated the involvement of circulating blood and progenitor cells in the atherosclerosis-enhancing activity of ACE and the AT 1 r...

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Section: Discussionmentioning

confidence: 74%

Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis

Alla

Langer

Elzahwy

et al. 2010

Journal of Biological Chemistry

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“…However, only the nonspecific small-molecule antagonist TAK-779, which inhibits chemochine CXC motif receptor (CXCR3) and CCR5 in addition to CCR2, and the broad-spectrum antiinflammatory compound propagermanium have been used to examine the effects of pharmacological blockade of CCR2 function. 15,16,39,40 In each of these studies, the compounds had significant effects on lesion development; however, the lack of specificity makes it impossible to attribute this to blockade of CCR2. Although clinical trials for CCR2 antagonists have primarily focused on inflammatory or metabolic disorders, including rheumatoid arthritis, multiple sclerosis, and diabetes mellitus, 33 there has also been an effort to examine a CCR2-blocking antibody in patients at risk for atherosclerotic cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein E ^−/− Mouse: Magnetic Resonance Imaging Assessment

Olzinski

Turner

Bernard

et al. 2010

ATVB

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Purpose-This study assessed the pharmacological effect of a novel selective C-C chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model. Methods and Results-Apolipoprotein E Ϫ/Ϫ mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (PϽ0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (PϽ0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (PϽ0.05). Conclusion-An

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“…39) TLK-19705 is also known to moderately inhibit CCL4-induced macrophage migration. 40) Recently, the importance of multiple blockade of chemokine signaling pathways for prevention of plaque formation was exemplified by a CCR5 and CXCR3 dual antagonist, TAK-779, 45) and the involvement of other chemokines such as CCL5, CCL18 and CX 3 CL1 has been reported. 10,46,47) Therefore, it is likely that the beneficial effects of PG and TLK-19705 on atherosclerosis are partly due to their dual inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

A Novel C–C Chemokine Receptor 2 Antagonist Prevents Progression of Albuminuria and Atherosclerosis in Mouse Models

Okamoto

Fuchigami

Suzuki

et al. 2012

Biological & Pharmaceutical Bulletin

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A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice

Cited by 11 publications

References 42 publications

Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis

Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis

Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein E ^−/− Mouse: Magnetic Resonance Imaging Assessment

A Novel C–C Chemokine Receptor 2 Antagonist Prevents Progression of Albuminuria and Atherosclerosis in Mouse Models

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A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice

Cited by 11 publications

References 42 publications

Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis

Angiotensin-converting Enzyme Inhibition Down-regulates the Pro-atherogenic Chemokine Receptor 9 (CCR9)-Chemokine Ligand 25 (CCL25) Axis

Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein E −/− Mouse: Magnetic Resonance Imaging Assessment

A Novel C–C Chemokine Receptor 2 Antagonist Prevents Progression of Albuminuria and Atherosclerosis in Mouse Models

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Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein E ^−/− Mouse: Magnetic Resonance Imaging Assessment