P623RGS-1 modulates leukocyte trafficking in atherosclerosis and aortic aneurysm formation through chemokine receptor desensitisation.

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 Signalling-1 (RGS1) acts to deactivate the intracellular response to sustained chemokine stimulation. We have found that RGS-1 is up-regulated with atherosclerotic plaque progression and with monocyte-macrophage activation. However little is known about the role of RGS-1 in macrophage function in vivo. Rgs1 deficient macrophages have significantly enhanced migratory responses to atherogenic chemokines (p<0.05) and have impaired desensitisation to repeated chemokine re-stimulation (p<0.001). In vivo, RGS1 has a role in the accumulation of macrophages in atherosclerotic lesions and during Angiotensin-II aortic aneurysm rupture. In the absence of RGS1, atherosclerosis is attenuated in early lesions in the aortic root and aortas of ApoE-/- mice (p<0.001) which is accompanied by fewer macrophages in the aortic root. Rgs1-/-ApoE-/- mice are protected from Angiotensin-II induced aneurysm rupture compared to ApoE-/- mice with 94% survival vs. 56% (p=0.0147). Rgs1-/-ApoE-/- mice have significantly fewer CD11b+ myeloid cells and CD14+ macrophages in aortas than ApoE-/- mice (p