Reversal of Vascular Macrophage Accumulation and Hypertension by a CCR2 Antagonist in Deoxycorticosterone/Salt-Treated Mice

Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. In the present study, we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with ANG II (0.7 mg·kg−1·day−1, 14 days) had elevated systolic BP (158 ± 3 mmHg) compared with saline-treated animals (122 ± 3 mmHg). Flow cytometry revealed that ANG II infusion increased numbers of CD45+CD11b+Ly6Chi monocytes and CD45+CD11b+F4/80+ macrophages by 10- and 2-fold, respectively. The majority of macrophages were positive for the M2 marker CD206 but negative for the M1 marker inducible nitric oxide synthase. Expression of other M2 genes (arginase-1, Fc receptor-like S scavenger receptor, and receptor-1) was elevated in aortas from ANG II-treated mice, whereas M1 genes [TNF and chemokine (C-X-C motif) ligand 2] were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed chemokine (C-C motif) receptor 2 (CCR2) to be upregulated in aortas from ANG II-treated mice, while flow cytometry identified Ly6Chi monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344; 30 mg·kg−1·day−1), 7 days after the commencement of ANG II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss, and BP in ANG II-treated mice. Thus, ANG II-dependent hypertension in mice is associated with Ly6Chi monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents ANG II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.

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Faculty Opinions recommendation of CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718089072.793518339 ◽

2016 ◽

Author(s):

Kar Neng Lai

Keyword(s):

Ccr2 Antagonist

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Faculty Opinions recommendation of Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735224984.793557250 ◽

2019 ◽

Author(s):

John Lowe

Keyword(s):

Conformational Switching ◽

Switching Mechanism ◽

Ccr2 Antagonist

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Analgesic effects evoked by a CCR2 antagonist or an anti-CCL2 antibody in inflamed mice

Fundamental and Clinical Pharmacology ◽

10.1111/fcp.12182 ◽

2016 ◽

Vol 30 (3) ◽

pp. 235-247 ◽

Cited By ~ 7

Author(s):

María Llorián-Salvador ◽

Marta Pevida ◽

Sara González-Rodríguez ◽

Ana Lastra ◽

María-Teresa Fernández-García ◽

...

Keyword(s):

Analgesic Effects ◽

Ccr2 Antagonist

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PP2Acα promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNFα production

Cell Death and Differentiation ◽

10.1038/s41418-021-00780-5 ◽

2021 ◽

Author(s):

Yan Liang ◽

Xiaoli Sun ◽

Mingjie Wang ◽

Qingmiao Lu ◽

Mengru Gu ◽

...

Keyword(s):

Cell Death ◽

Tubular Cell ◽

Kidney Fibrosis ◽

Tubular Cells ◽

Ureter Obstruction ◽

Underlying Mechanisms ◽

Factor Α ◽

Rap1 Activation ◽

Necrosis Factor ◽

Macrophage Accumulation

AbstractMacrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα−/− macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.

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Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

Scientific Reports ◽

10.1038/s41598-021-94169-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Thanachai Methatham ◽

Shota Tomida ◽

Natsuka Kimura ◽

Yasushi Imai ◽

Kenichi Aizawa

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Left Ventricular ◽

Cardiac Wall ◽

Macrophage Marker ◽

Glycolysis Pathway ◽

Canonical Wnt ◽

Macrophage Accumulation

AbstractIn heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

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