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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−/−ApoE−/− mice are protected from Ang II-induced aortic aneurysm rupture.(a) ApoE−/− and Rgs1−/−ApoE−/− mice were infused with Ang II or saline for 14 days. Representative photographs showing features of aneurysms induced by Ang II in surviving mice. The arrows indicate typical aneurysms in ApoE−/− mice. There was no aneurysm formation in the control saline-treated group in both ApoE−/− and Rgs1−/−ApoE−/− mice (n=3–4). (b) Survival curve of ApoE−/− and Rgs1−/−ApoE−/− mice during Ang II (0.8 mg kg−1 per day) infusion. All deaths were due to aortic rupture (c) The incidence of Ang II-induced aortic aneurysms in ApoE−/− mice compared with Rgs1−/−ApoE−/− mice. (d) The systolic blood pressure (BP) of ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. (e) Survival curve of chimeric ApoE−/− mice during Ang II infusion (3 mg kg−1 per day). All deaths were due to aortic rupture. (f) The incidence of Ang II-induced aortic aneurysms in chimeric ApoE−/− mice. (g) The systolic blood pressure of chimeric ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. *P<0.05 in b,e calculated using the χ2-test (n=14–19). *P<0.05 in d,g calculated using one-way analysis of variance of area under the curve (n=5–6). Data in d,g are expressed as mean±s.e.m.
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f5: Rgs1−/−ApoE−/− mice are protected from Ang II-induced aortic aneurysm rupture.(a) ApoE−/− and Rgs1−/−ApoE−/− mice were infused with Ang II or saline for 14 days. Representative photographs showing features of aneurysms induced by Ang II in surviving mice. The arrows indicate typical aneurysms in ApoE−/− mice. There was no aneurysm formation in the control saline-treated group in both ApoE−/− and Rgs1−/−ApoE−/− mice (n=3–4). (b) Survival curve of ApoE−/− and Rgs1−/−ApoE−/− mice during Ang II (0.8 mg kg−1 per day) infusion. All deaths were due to aortic rupture (c) The incidence of Ang II-induced aortic aneurysms in ApoE−/− mice compared with Rgs1−/−ApoE−/− mice. (d) The systolic blood pressure (BP) of ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. (e) Survival curve of chimeric ApoE−/− mice during Ang II infusion (3 mg kg−1 per day). All deaths were due to aortic rupture. (f) The incidence of Ang II-induced aortic aneurysms in chimeric ApoE−/− mice. (g) The systolic blood pressure of chimeric ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. *P<0.05 in b,e calculated using the χ2-test (n=14–19). *P<0.05 in d,g calculated using one-way analysis of variance of area under the curve (n=5–6). Data in d,g are expressed as mean±s.e.m.

Mentions: To further investigate the contribution of RGS1 to Ang II-induced aortic aneurysm formation, we performed 14-day Ang II infusions in Rgs1−/−ApoE−/− and ApoE−/− mice, since most aortic ruptures occur within the first 7 days20. ApoE−/− mice were significantly more susceptible to aortic aneurysm rupture in comparison with Rgs1−/−ApoE−/− mice, with 56% survival in ApoE−/− mice versus 94% in the Rgs1−/−ApoE−/−group (Fig. 5a,b). We also noted aneurysms at the study end point in surviving ApoE−/− mice, which were absent in Rgs1−/−ApoE−/− mice (Fig. 5c). No difference in circulating, bone marrow and spleen monocyte numbers were found between Rgs1−/−ApoE−/− and ApoE−/− mice, indicating that the observed effect was not due to a change in monocyte numbers elsewhere (Supplementary Fig. 8). Previous studies have demonstrated that Ang II infusion increases systolic blood pressure in mice7. Therefore, to determine whether Rgs1 deficiency affects Ang II-mediated increases in blood pressure, we measured the systolic blood pressure in both groups. Between days 2 and 10, Ang II treatment increased systolic blood pressure in Rgs1−/−ApoE−/− mice more than in ApoE−/− mice (Fig. 5d), demonstrating that protection from aneurysm formation in Rgs1−/−ApoE−/− mice occurs despite a greater rise in blood pressure and through mechanisms that are independent of Ang II-induced hypertension.


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−/−ApoE−/− mice are protected from Ang II-induced aortic aneurysm rupture.(a) ApoE−/− and Rgs1−/−ApoE−/− mice were infused with Ang II or saline for 14 days. Representative photographs showing features of aneurysms induced by Ang II in surviving mice. The arrows indicate typical aneurysms in ApoE−/− mice. There was no aneurysm formation in the control saline-treated group in both ApoE−/− and Rgs1−/−ApoE−/− mice (n=3–4). (b) Survival curve of ApoE−/− and Rgs1−/−ApoE−/− mice during Ang II (0.8 mg kg−1 per day) infusion. All deaths were due to aortic rupture (c) The incidence of Ang II-induced aortic aneurysms in ApoE−/− mice compared with Rgs1−/−ApoE−/− mice. (d) The systolic blood pressure (BP) of ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. (e) Survival curve of chimeric ApoE−/− mice during Ang II infusion (3 mg kg−1 per day). All deaths were due to aortic rupture. (f) The incidence of Ang II-induced aortic aneurysms in chimeric ApoE−/− mice. (g) The systolic blood pressure of chimeric ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. *P<0.05 in b,e calculated using the χ2-test (n=14–19). *P<0.05 in d,g calculated using one-way analysis of variance of area under the curve (n=5–6). Data in d,g are expressed as mean±s.e.m.
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Related In: Results  -  Collection

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Show All Figures
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f5: Rgs1−/−ApoE−/− mice are protected from Ang II-induced aortic aneurysm rupture.(a) ApoE−/− and Rgs1−/−ApoE−/− mice were infused with Ang II or saline for 14 days. Representative photographs showing features of aneurysms induced by Ang II in surviving mice. The arrows indicate typical aneurysms in ApoE−/− mice. There was no aneurysm formation in the control saline-treated group in both ApoE−/− and Rgs1−/−ApoE−/− mice (n=3–4). (b) Survival curve of ApoE−/− and Rgs1−/−ApoE−/− mice during Ang II (0.8 mg kg−1 per day) infusion. All deaths were due to aortic rupture (c) The incidence of Ang II-induced aortic aneurysms in ApoE−/− mice compared with Rgs1−/−ApoE−/− mice. (d) The systolic blood pressure (BP) of ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. (e) Survival curve of chimeric ApoE−/− mice during Ang II infusion (3 mg kg−1 per day). All deaths were due to aortic rupture. (f) The incidence of Ang II-induced aortic aneurysms in chimeric ApoE−/− mice. (g) The systolic blood pressure of chimeric ApoE−/− and Rgs1−/−ApoE−/− mice that were infused with Ang II (0.8 mg kg−1 per day) over 14 days. *P<0.05 in b,e calculated using the χ2-test (n=14–19). *P<0.05 in d,g calculated using one-way analysis of variance of area under the curve (n=5–6). Data in d,g are expressed as mean±s.e.m.
Mentions: To further investigate the contribution of RGS1 to Ang II-induced aortic aneurysm formation, we performed 14-day Ang II infusions in Rgs1−/−ApoE−/− and ApoE−/− mice, since most aortic ruptures occur within the first 7 days20. ApoE−/− mice were significantly more susceptible to aortic aneurysm rupture in comparison with Rgs1−/−ApoE−/− mice, with 56% survival in ApoE−/− mice versus 94% in the Rgs1−/−ApoE−/−group (Fig. 5a,b). We also noted aneurysms at the study end point in surviving ApoE−/− mice, which were absent in Rgs1−/−ApoE−/− mice (Fig. 5c). No difference in circulating, bone marrow and spleen monocyte numbers were found between Rgs1−/−ApoE−/− and ApoE−/− mice, indicating that the observed effect was not due to a change in monocyte numbers elsewhere (Supplementary Fig. 8). Previous studies have demonstrated that Ang II infusion increases systolic blood pressure in mice7. Therefore, to determine whether Rgs1 deficiency affects Ang II-mediated increases in blood pressure, we measured the systolic blood pressure in both groups. Between days 2 and 10, Ang II treatment increased systolic blood pressure in Rgs1−/−ApoE−/− mice more than in ApoE−/− mice (Fig. 5d), demonstrating that protection from aneurysm formation in Rgs1−/−ApoE−/− mice occurs despite a greater rise in blood pressure and through mechanisms that are independent of Ang II-induced hypertension.

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