Early atheroprotection through fostamatinib fails in established disease when local macrophage proliferation dominates lesion progression

C. Härdtner1, A. Lindau1, B. Dufner1, N. Hoppe1, F. K. Swirski2, P. Libby2, C. S. Robbins3, C. Bode1, A. Zirlik1, I. Hilgendorf1 (1Freiburg, Germany, 2Boston, USA, 3Toronto, Canada)

Vascular Wall
Date: 17.02.2017,
Time: 08:00 - 09:15

Objective: Atherosclerosis is a chronic inflammtory disease driven by the accumulation of lipid-loaden macrophages in vascular lesions. Under hypercholesterolemic conditions murine Ly6Chigh monocytes surge in blood and spleen, infiltrate nascent atherosclerotic lesions and differentiate into macrophages under the influence of myeloid growth factors. In established atherosclerosic plaques macrophage accumulate primarily through local proliferation independently of myeloid growth factors GM-CSF and IL3. Spleen tyrosine kinase (SYK) is involved in down stream signaling of these growth factors. We therefore tested the effects of SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in ApoE–/– mice during early and established atherosclerosis.


Results: ApoE–/– mice fed a high cholesterol diet (HCD) supplemented with fostamatinib 0.3% (w/w) for 8 weeks developed less atherosclerosis throughout the aorta. Aortic root histology and flow cytometry of aortic tissue lysates confirmed a reduction in macrophage content and Ly6Chigh monocyte infiltrate. In accord, hypercholesterolemia-associated Ly6Chigh monocytosis was almost completely abolished with fostamatinib treatment. GM-CSF/IL3 stimulated medullary and extramedullary myeloid progenitor proliferation was attenuated without signs of monocytotoxicity. Moreover, fostamatinib inhibited inflammatory cell recruitment and adhesion to the vessel wall. In ApoE–/– mice with established atherosclerosis, however, fostamatinib did not prevent macrophage accumulation and lesion progression despite a significant reduction in monocyte counts as lesional macrophage proliferation, death and egress remained unaffected.

Conclusion: Our study exemplifies how potent inhibition of hypercholesterolemia associated monocytosis attenuates de novo atherogenesis but not lesion progression in established disease when local macrophage proliferation dominates lesion turnover.