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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 atherosclerosis and macrophage content in ApoE−/−mice.(a) Atherosclerotic plaque in the aortic roots of 9-week-old mice on a chow diet. Microscopy of massons trichrome stained aortic root lesions. (b) Galectin-3-positive macrophage content in the aortic roots of 9-week-old mice on a chow diet. Microscopy of Galectin-3-stained aortic root lesions. (c) En face atherosclerotic plaque in the aortas of 16-week-old mice on a chow diet. Microscopy of en face Oil Red O staining of aortic arches of descending aortas. Each symbol represents an individual mouse (n=7–8 per group). Scale bars indicate 0.25 mm for aortic roots and 1 mm for aortas. Arrows indicate atherosclerotic lesions. Values are expressed as mean±s.e.m. ***P<0.001, **P<0.01, *P<0.05 calculated using the Student’s t-test.
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f3: Rgs1 deficiency reduces atherosclerosis and macrophage content in ApoE−/−mice.(a) Atherosclerotic plaque in the aortic roots of 9-week-old mice on a chow diet. Microscopy of massons trichrome stained aortic root lesions. (b) Galectin-3-positive macrophage content in the aortic roots of 9-week-old mice on a chow diet. Microscopy of Galectin-3-stained aortic root lesions. (c) En face atherosclerotic plaque in the aortas of 16-week-old mice on a chow diet. Microscopy of en face Oil Red O staining of aortic arches of descending aortas. Each symbol represents an individual mouse (n=7–8 per group). Scale bars indicate 0.25 mm for aortic roots and 1 mm for aortas. Arrows indicate atherosclerotic lesions. Values are expressed as mean±s.e.m. ***P<0.001, **P<0.01, *P<0.05 calculated using the Student’s t-test.

Mentions: Since macrophage recruitment is a critical step in atherogenesis, and given that Rgs1-deficient macrophages showed an increased migratory response to atherogenic chemokines in vitro, we hypothesized that Rgs1−/−ApoE−/− mice would develop larger atherosclerotic lesions than ApoE−/− mice as a result of enhanced leukocyte recruitment. To test this hypothesis, we quantified atherosclerotic plaque in Rgs1−/−ApoE−/−and ApoE−/− mice at two anatomical sites—the aortic root and the descending aorta. However, in contrast to our hypothesis, the absence of Rgs1 significantly reduced both atherosclerotic plaque formation in the aortic root of ApoE−/− mice (Fig. 3a) and reduced plaque macrophage content, quantified by Galectin-3-positive macrophage immunostaining (Fig. 3b) in 9-week-old animals. Similar results were observed by en face analysis of the descending aorta, where plaques develop later in 16-week-old animals. Rgs1−/−ApoE−/− mice had smaller lesions in comparison with ApoE−/− littermates (Fig. 3c). No differences in lesion size or macrophage content were observed in the aortic root in mice fed a chow diet for 16 weeks or mice on a western-type diet (Supplementary Fig. 3). In addition, no CD3 T-lymphocyte infiltration in the aortic root was observed at any time point (Supplementary Fig. 4). Since Rgs1 has been reported to contribute to T-cell migration17, we also characterized Treg cells and antigen-specific cytokine responses of Th1 and Th17 cells in Rgs1−/−ApoE−/− and ApoE−/− mice after co-stimulation with anti-CD3/CD28, and found no significant difference between groups (Supplementary Figs 5 and 6). No difference in total serum cholesterol levels or circulating monocyte numbers were found between Rgs1−/−ApoE−/− and ApoE−/− mice, indicating that the observed effect was not due to a change in plasma lipids or monocyte numbers, respectively (Supplementary Table 2). In addition, no differences in in vitro foam cell formation were observed between Rgs1−/−ApoE−/− and ApoE−/− macrophages treated with acLDL over 24 h (Supplementary Fig. 7).


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 atherosclerosis and macrophage content in ApoE−/−mice.(a) Atherosclerotic plaque in the aortic roots of 9-week-old mice on a chow diet. Microscopy of massons trichrome stained aortic root lesions. (b) Galectin-3-positive macrophage content in the aortic roots of 9-week-old mice on a chow diet. Microscopy of Galectin-3-stained aortic root lesions. (c) En face atherosclerotic plaque in the aortas of 16-week-old mice on a chow diet. Microscopy of en face Oil Red O staining of aortic arches of descending aortas. Each symbol represents an individual mouse (n=7–8 per group). Scale bars indicate 0.25 mm for aortic roots and 1 mm for aortas. Arrows indicate atherosclerotic lesions. Values are expressed as mean±s.e.m. ***P<0.001, **P<0.01, *P<0.05 calculated using the Student’s t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374153&req=5

f3: Rgs1 deficiency reduces atherosclerosis and macrophage content in ApoE−/−mice.(a) Atherosclerotic plaque in the aortic roots of 9-week-old mice on a chow diet. Microscopy of massons trichrome stained aortic root lesions. (b) Galectin-3-positive macrophage content in the aortic roots of 9-week-old mice on a chow diet. Microscopy of Galectin-3-stained aortic root lesions. (c) En face atherosclerotic plaque in the aortas of 16-week-old mice on a chow diet. Microscopy of en face Oil Red O staining of aortic arches of descending aortas. Each symbol represents an individual mouse (n=7–8 per group). Scale bars indicate 0.25 mm for aortic roots and 1 mm for aortas. Arrows indicate atherosclerotic lesions. Values are expressed as mean±s.e.m. ***P<0.001, **P<0.01, *P<0.05 calculated using the Student’s t-test.
Mentions: Since macrophage recruitment is a critical step in atherogenesis, and given that Rgs1-deficient macrophages showed an increased migratory response to atherogenic chemokines in vitro, we hypothesized that Rgs1−/−ApoE−/− mice would develop larger atherosclerotic lesions than ApoE−/− mice as a result of enhanced leukocyte recruitment. To test this hypothesis, we quantified atherosclerotic plaque in Rgs1−/−ApoE−/−and ApoE−/− mice at two anatomical sites—the aortic root and the descending aorta. However, in contrast to our hypothesis, the absence of Rgs1 significantly reduced both atherosclerotic plaque formation in the aortic root of ApoE−/− mice (Fig. 3a) and reduced plaque macrophage content, quantified by Galectin-3-positive macrophage immunostaining (Fig. 3b) in 9-week-old animals. Similar results were observed by en face analysis of the descending aorta, where plaques develop later in 16-week-old animals. Rgs1−/−ApoE−/− mice had smaller lesions in comparison with ApoE−/− littermates (Fig. 3c). No differences in lesion size or macrophage content were observed in the aortic root in mice fed a chow diet for 16 weeks or mice on a western-type diet (Supplementary Fig. 3). In addition, no CD3 T-lymphocyte infiltration in the aortic root was observed at any time point (Supplementary Fig. 4). Since Rgs1 has been reported to contribute to T-cell migration17, we also characterized Treg cells and antigen-specific cytokine responses of Th1 and Th17 cells in Rgs1−/−ApoE−/− and ApoE−/− mice after co-stimulation with anti-CD3/CD28, and found no significant difference between groups (Supplementary Figs 5 and 6). No difference in total serum cholesterol levels or circulating monocyte numbers were found between Rgs1−/−ApoE−/− and ApoE−/− mice, indicating that the observed effect was not due to a change in plasma lipids or monocyte numbers, respectively (Supplementary Table 2). In addition, no differences in in vitro foam cell formation were observed between Rgs1−/−ApoE−/− and ApoE−/− macrophages treated with acLDL over 24 h (Supplementary Fig. 7).

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