Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice

Abstract

Objective-To determine the significance of fibroblast growth factor receptor (FGFR) expression for the development of atherosclerotic lesions in apoE-deficient (apoE Ϫ/Ϫ ) mice. Methods and Results-ApoEϪ/Ϫ mice fed a high-fat diet were administered the FGFR tyrosine kinase inhibitor SU5402 (25 mg/kg/d sc), which inhibited neointima growth by 85%. We measured its effects on lesion size at the aortic sinus, macrophage and smooth muscle cell (SMC) accumulation, the expression of monocyte chemotactic and retention factors, as well as its effects on FGFR expression/phosphorylation. FGFR tyrosine kinase inhibition reduced phosphorylated FGFRs in lesions by 90%, associated with a 65% reduction in lesion size measured using Oil Red O. Macrophages and SMCs within lesions were reduced by 58% and 78%, respectively. Monocyte chemotactic protein-1 (MCP-1) expression was also reduced, as was the expression of hyaluronan synthase, cyclooxygenase-2, CD36, and endothelial monocyte-activating polypeptide-II. Although 3 FGFR types were expressed in lesions, the effects of SU5402 could be attributed largely to inhibition of FGFR-1 phosphorylation. Conclusions-Atherosclerotic lesions in apoEϪ/Ϫ mice express multiple FGFRs and an active FGF:FGFR-1 signaling system that promotes atherosclerosis development via increased SMC proliferation, and by augmenting macrophage accumulation via increased expression of MCP-1 and factors promoting macrophage retention in lesions.

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

“…Sections were stained with oil red O for lipid content. 20 Immunohistochemistry was performed as previously described. 21 Briefly, the sections were fixed in cold (Ϫ20°C) acetone for 20 minutes and then sequentially incubated in 3% H 2 O 2 in PBS, 10% normal goat serum (NGS/PBS), and biotin/avidin blocking reagents (Vector Laboratories).…”

Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents

“…To assess the potential effects of the FGFR1 inhibitor SU5402 on established PH, adult male Wistar rats (200-250 g) were given MCT (60 mg/kg s.c.), left untreated for 21 days, then randomly divided into 2 groups (10 animals in each group), of which one was treated with SU5402 (25 mg/kg/day) and the other given the vehicle, from day 21 to day 42. All treatments were given once a day by s.c. injection (47).…”

Endothelial FGF receptor signaling: angiogenic versus atherogenic effects

“…Probably the most direct correlation between FGFR2 and atherogenesis was reported by Raj et al (9). In this study, ApoE-knockout mice were fed an FGF-2 tyrosine kinase inhibitor SU-5402.…”

“…Therefore, the significance of the study by Che et al (2) is not so much that FGFR2 is associated with atherosclerosis, which has been previously reported (9), but that it more precisely identifies the signaling processes by which FGFR2 affects atherogenesis. This then elegantly constructs a working model of how FGFR2 may affect atherogenesis.…”

“…These mice had less atherosclerosis than control ApoE-knockout mice receiving no inhibitor. Unlike the study of Che et al (2), the study by Raj et al (9) included evidence that FGFR2 affects plaque inflammation and oxidation processes. This was illustrated by a reduced number of macrophages, a reduced expression of monocyte chemoattractant protein-1, and a reduced expression of cyclooxygenase and CD36 in the SU-5402-treated mice.…”