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-/-) mice.

METHODS AND RESULTS:

ApoE-/- 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 apoE-/- 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.

• Authors: Tina Raj, Peter Kanellakis, Giovanna Pomilio, Garry Jennings, Alex Bobik, Alex Agrotis
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 26 Issue 8 Pg. 1845-51 (Aug 2006) ISSN: 1524-4636 [Electronic] United States
• PMID: 16709940 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Chemokines
• Dietary Fats
• Enzyme Inhibitors
• Pyrroles
• Receptors, Fibroblast Growth Factor
• SU 5402
• Vascular Cell Adhesion Molecule-1
• Fibroblast Growth Factors
• Glucuronosyltransferase
• Hyaluronan Synthases
• Protein-Tyrosine Kinases

Topics

• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (etiology, metabolism, pathology)
• Chemokines (metabolism)
• Dietary Fats (administration & dosage)
• Enzyme Inhibitors (pharmacology)
• Fibroblast Growth Factors (metabolism)
• Glucuronosyltransferase (metabolism)
• Hyaluronan Synthases
• Macrophages (pathology)
• Male
• Mice
• Mice, Knockout
• Monocytes (metabolism, pathology)
• Myocytes, Smooth Muscle (pathology)
• Phosphorylation
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrroles (pharmacology)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, metabolism)
• Sinus of Valsalva (drug effects, pathology)
• Tunica Intima (drug effects, growth & development)
• Vascular Cell Adhesion Molecule-1 (metabolism)