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RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling.

Patel J, McNeill E, Douglas G, Hale AB, de Bono J, Lee R, Iqbal AJ, Regan-Komito D, Stylianou E, Greaves DR, Channon KM - Nat Commun (2015)

Bottom Line: Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation.Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling.Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

ABSTRACT
Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention and accumulation of macrophages in the vascular wall remain unclear. Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation. Here we show that Rgs1 is upregulated in atherosclerotic plaque and aortic aneurysms. Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling. In early atherosclerotic lesions, Rgs1 regulates macrophage accumulation and is required for the formation and rupture of Angiotensin II-induced aortic aneurysms, through effects on leukocyte retention. Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

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Rgs1 deficiency reduces aortic inflammatory cell trafficking in Ang II-treated ApoE−/− mice via CCR2.Flow cytometric analysis of aortic leukocytes in ApoE−/− and Rgs1−/−ApoE−/− mice that received (a) saline or (b) Ang II infusion at 0.8 mg kg−1 per day for 5 days. Representative dot plots shown for gated aortic cells of each positive population from ApoE−/− and Rgs1−/−ApoE−/− mice with representative percentages. Labels on both axes are on a log scale. Quantification of the numbers of (c) CD45+ cells (d) CD45+CD14+CD11b+ cells and (e) CD45+CD14+CD11b+CCR2+ cells in saline-treated and Ang II-infused mice. Each symbol represents an individual mouse (n=3–4 for saline and n=4–6 for Ang II). There were two deaths from aneurysm rupture in the ApoE−/− Ang II group. (f) The expression of CCR2 on CD45+CD14+CD11b+ cells in the aorta of saline-treated and Ang II-infused mice (MFI, mean fluorescence intensity). Values are expressed as mean±s.e.m. *P<0.05 and **P<0.01 calculated using the Student’s t-test.
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f4: Rgs1 deficiency reduces aortic inflammatory cell trafficking in Ang II-treated ApoE−/− mice via CCR2.Flow cytometric analysis of aortic leukocytes in ApoE−/− and Rgs1−/−ApoE−/− mice that received (a) saline or (b) Ang II infusion at 0.8 mg kg−1 per day for 5 days. Representative dot plots shown for gated aortic cells of each positive population from ApoE−/− and Rgs1−/−ApoE−/− mice with representative percentages. Labels on both axes are on a log scale. Quantification of the numbers of (c) CD45+ cells (d) CD45+CD14+CD11b+ cells and (e) CD45+CD14+CD11b+CCR2+ cells in saline-treated and Ang II-infused mice. Each symbol represents an individual mouse (n=3–4 for saline and n=4–6 for Ang II). There were two deaths from aneurysm rupture in the ApoE−/− Ang II group. (f) The expression of CCR2 on CD45+CD14+CD11b+ cells in the aorta of saline-treated and Ang II-infused mice (MFI, mean fluorescence intensity). Values are expressed as mean±s.e.m. *P<0.05 and **P<0.01 calculated using the Student’s t-test.

Mentions: To determine the effect of Rgs1 deficiency on the early influx of myeloid cells into the aortic wall during inflammation, we infused Angiotensin II (Ang II) at 0.8 mg kg−1 per day using subcutaneous mini pumps in ApoE−/− mice, a model known to induce acute aortic leukocyte recruitment and increase blood pressure. Leukocyte content in the thoracic aortas of Rgs1−/−ApoE−/− and ApoE−/− mice following Ang II infusion was quantified by enzymatic digestion and flow cytometry (Fig. 4a,b)1819. In Rgs1-deficient mice, CD45+ leukocytes and CD11b+ myeloid cells in aortas were reduced more than 10-fold compared with ApoE−/− mice after 5 days of Ang II infusion (Fig. 4c–e). These cells were CD14+CCR2+, indicative of recruited monocyte–macrophages. Since Ang II mediates monocyte recruitment to the aorta, and AAA formation is largely driven by CCR2 in contrast to CCR5 (refs 6, 18, 19), we assessed CCR2 expression on these cells. We found that CCR2 surface expression on macrophages in the aortas was significantly decreased following Ang II treatment in ApoE−/− mice (Fig. 4f). However, no reduction in cell surface CCR2 was observed in macrophages from Rgs1−/−ApoE−/− mice, indicating a lack of receptor desensitization in Rgs1−/−ApoE−/− mice. Furthermore, between days 3 and 5 of Ang II infusion, two out of six ApoE−/− mice died from aneurysm rupture, but no deaths occurred in Rgs1−/−ApoE−/− mice, indicating that Rgs1 deficiency confers protection from Ang II-induced aortic aneurysm rupture.


RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling.

Patel J, McNeill E, Douglas G, Hale AB, de Bono J, Lee R, Iqbal AJ, Regan-Komito D, Stylianou E, Greaves DR, Channon KM - Nat Commun (2015)

Rgs1 deficiency reduces aortic inflammatory cell trafficking in Ang II-treated ApoE−/− mice via CCR2.Flow cytometric analysis of aortic leukocytes in ApoE−/− and Rgs1−/−ApoE−/− mice that received (a) saline or (b) Ang II infusion at 0.8 mg kg−1 per day for 5 days. Representative dot plots shown for gated aortic cells of each positive population from ApoE−/− and Rgs1−/−ApoE−/− mice with representative percentages. Labels on both axes are on a log scale. Quantification of the numbers of (c) CD45+ cells (d) CD45+CD14+CD11b+ cells and (e) CD45+CD14+CD11b+CCR2+ cells in saline-treated and Ang II-infused mice. Each symbol represents an individual mouse (n=3–4 for saline and n=4–6 for Ang II). There were two deaths from aneurysm rupture in the ApoE−/− Ang II group. (f) The expression of CCR2 on CD45+CD14+CD11b+ cells in the aorta of saline-treated and Ang II-infused mice (MFI, mean fluorescence intensity). Values are expressed as mean±s.e.m. *P<0.05 and **P<0.01 calculated using the Student’s t-test.
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f4: Rgs1 deficiency reduces aortic inflammatory cell trafficking in Ang II-treated ApoE−/− mice via CCR2.Flow cytometric analysis of aortic leukocytes in ApoE−/− and Rgs1−/−ApoE−/− mice that received (a) saline or (b) Ang II infusion at 0.8 mg kg−1 per day for 5 days. Representative dot plots shown for gated aortic cells of each positive population from ApoE−/− and Rgs1−/−ApoE−/− mice with representative percentages. Labels on both axes are on a log scale. Quantification of the numbers of (c) CD45+ cells (d) CD45+CD14+CD11b+ cells and (e) CD45+CD14+CD11b+CCR2+ cells in saline-treated and Ang II-infused mice. Each symbol represents an individual mouse (n=3–4 for saline and n=4–6 for Ang II). There were two deaths from aneurysm rupture in the ApoE−/− Ang II group. (f) The expression of CCR2 on CD45+CD14+CD11b+ cells in the aorta of saline-treated and Ang II-infused mice (MFI, mean fluorescence intensity). Values are expressed as mean±s.e.m. *P<0.05 and **P<0.01 calculated using the Student’s t-test.
Mentions: To determine the effect of Rgs1 deficiency on the early influx of myeloid cells into the aortic wall during inflammation, we infused Angiotensin II (Ang II) at 0.8 mg kg−1 per day using subcutaneous mini pumps in ApoE−/− mice, a model known to induce acute aortic leukocyte recruitment and increase blood pressure. Leukocyte content in the thoracic aortas of Rgs1−/−ApoE−/− and ApoE−/− mice following Ang II infusion was quantified by enzymatic digestion and flow cytometry (Fig. 4a,b)1819. In Rgs1-deficient mice, CD45+ leukocytes and CD11b+ myeloid cells in aortas were reduced more than 10-fold compared with ApoE−/− mice after 5 days of Ang II infusion (Fig. 4c–e). These cells were CD14+CCR2+, indicative of recruited monocyte–macrophages. Since Ang II mediates monocyte recruitment to the aorta, and AAA formation is largely driven by CCR2 in contrast to CCR5 (refs 6, 18, 19), we assessed CCR2 expression on these cells. We found that CCR2 surface expression on macrophages in the aortas was significantly decreased following Ang II treatment in ApoE−/− mice (Fig. 4f). However, no reduction in cell surface CCR2 was observed in macrophages from Rgs1−/−ApoE−/− mice, indicating a lack of receptor desensitization in Rgs1−/−ApoE−/− mice. Furthermore, between days 3 and 5 of Ang II infusion, two out of six ApoE−/− mice died from aneurysm rupture, but no deaths occurred in Rgs1−/−ApoE−/− mice, indicating that Rgs1 deficiency confers protection from Ang II-induced aortic aneurysm rupture.

Bottom Line: Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation.Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling.Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

ABSTRACT
Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention and accumulation of macrophages in the vascular wall remain unclear. Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation. Here we show that Rgs1 is upregulated in atherosclerotic plaque and aortic aneurysms. Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling. In early atherosclerotic lesions, Rgs1 regulates macrophage accumulation and is required for the formation and rupture of Angiotensin II-induced aortic aneurysms, through effects on leukocyte retention. Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease.

Show MeSH
Related in: MedlinePlus