Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression
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- 作者：Alexandra Lindau ; Carmen Härdtner ; Sonja P. Hergeth…
- 关键词：Atherosclerosis ; SYK ; Monocytes ; Macrophages ; Progenitors ; Proliferation ; Egress
- 刊名：Basic Research in Cardiology
- 出版年：2016
- 出版时间：March 2016
- 年：2016
- 卷：111
- 期：2
- 全文大小：2,829 KB
- 刊物类别：Medicine
- 刊物主题：Medicine & Public Health
Cardiology - 出版者：Springer Berlin / Heidelberg
- ISSN：1435-1803
文摘
Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6Chigh monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe−/− mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6Chigh monocytes and macrophages. SYK inhibition limited Ly6Chigh monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe−/− mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.