Abstract 3722: Deficiency Of Hck And Fgr Src Kinases Leads To Delayed Atherosclerosis In LDLr −/− Mice.
Hck and Fgr are members of the Src family of tyrosine kinases involved in regulation of immune activation and leukocyte function. In macrophages, deficiency of Hck and Fgr leads to impaired integrin signal transduction, altered cytoskeleton and reduced motility, while loss of Hck alone was seen to skew monocyte differentiation towards an M2 macrophage phenotype. In this study we evaluated the involvement of Hck and Fgr in atherosclerosis progression and composition. Female LDLr−/− mice were lethally irradiated and reconstituted one day later with bone marrow from either Hck/Fgr deficient or wild-type mice. After six weeks of recovery, the animals were fed an atherogenic diet during 13 weeks and then sacrificed for lesion analysis and ex-vivo experiments. Blood leukocyte counts were not different between groups. Peritoneal macrophages from the Hck/Fgr deficient mice exhibited a reduced migratory capacity (17 fold decrease compared to control, P=1E10 – 6) with altered formation of phylopodia. In agreement with these findings, reconstitution with Hck/Fgr deficient bone marrow resulted in 36% reduction in lesion size (P=0.02, n=10). Whereas necrotic core size did not differ between groups, fibrous caps and collagen content were markedly smaller in plaques of Fgr/Hck deficient chimeras, both as total area and as percentage of plaque area, suggesting a reduced stability (fibrous cap: −73% P=0.002 (absolute), 13 vs. 30%, P=0.0002 (relative); collagen: −87%, P=0.0001 (absolute); 2 vs. 11% P=0.0005 (relative)). In conclusion, deficiency of Hck and Fgr Src kinases leads to reduced atherosclerosis accompanied by reduced fibrosis and collagen contents, which may be partly attributable to impaired migration of monocytes to the plaque.