Abstract 149: Regulator of G-Protein Signaling-1 Modulates Leukocyte Trafficking in Atherosclerosis and Aortic Aneurysm Formation Through Chemokine Receptor Desensitization
The regulation of macrophage recruitment and retention into the vascular wall is critical in the progression of atherosclerosis and aortic aneurysm formation. This can be mediated by chemokine activation of multiple G-protein coupled receptors. The Regulator of G-Protein Signaling-1 (RGS1) acts to deactivate the intracellular response to sustained chemokine stimulation. We have found that RGS1 is upregulated with atherosclerotic plaque progression and with monocyte-macrophage activation but its role is unknown.
Rgs1-/- macrophages have significantly enhanced migratory responses to atherogenic chemokines and have impaired desensitization to chemokine re-stimulation (p<0.001). In vivo, RGS1 has a role in the accumulation of macrophages in atherosclerotic lesions and during Angiotensin II (AngII) aortic aneurysm rupture. In the absence of RGS1, atherosclerosis and macrophage accumulation is attenuated in early lesions in the aortic root and aortas of ApoE-/- mice (p<0.001). Rgs1-/- mice are protected from AngII induced aneurysm rupture compared to ApoE-/- mice with 94% survival vs. 56%. Rgs1-/- mice have significantly fewer CD11b+ myeloid cells and CD14+ macrophages in aortas than ApoE-/- mice (p<0.05) after 5 days of AngII infusion.
Following bone marrow transplantation, recipient mice receiving ApoE-/- bone marrow were more susceptible to aortic aneurysm rupture (p=0.0124), indicating bone marrow-derived RGS1 is required for aneurysm rupture. Furthermore, AngII treatment increased systolic blood pressure to a greater extent in Rgs1-/- mice than ApoE-/- mice suggesting aneurysm formation in these mice is independent of AngII induced hypertension and this is mediated by vascular-derived RGS1. To gain insight into the mechanism by which RGS1 regulates trafficking, we selectively labelled inflammatory monocytes in vivo to track their movement into aortas following AngII infusion. We found an accumulation of labelled CD45+ cells in the aortas of ApoE-/- mice from day 3 to day 5 but not in Rgs1-/- mice indicating RGS1 as a regulator of macrophage retention in aortic aneurysms.
These findings identify a novel role for RGS1 in leukocyte retention in vascular inflammation, highlighting RGS1 as a potential target in cardiovascular disease.
Author Disclosures: J. Patel: None. E. McNeill: None. G. Douglas: None. A. Hale: None. J. de Bono: None. D.R. Greaves: None. K.M. Channon: None.
- © 2014 by American Heart Association, Inc.