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Discoidin domain receptor 1 (ddr1) deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice.

Abstract：

:Collagens are abundant within the atherosclerotic plaque, where they contribute to lesion volume and mechanical stability and influence cell signaling. The discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds to collagen, is expressed in blood vessels, but evidence for a functional role during atherogenesis is incomplete. In the present study, we generated Ddr1(+/+);Ldlr(-/-) and Ddr1(-/-);Ldlr(-/-) mice and fed them an atherogenic diet for 12 or 24 weeks. Targeted deletion of Ddr1 resulted in a 50% to 60% reduction in atherosclerotic lesion area in the descending aorta at both 12 and 24 weeks. Ddr1(-/-);Ldlr(-/-) plaques exhibited accelerated deposition of fibrillar collagen and elastin at 12 weeks compared with Ddr1(+/+);Ldlr(-/-) plaques. Expression analysis of laser microdissected lesions in vivo, and of Ddr1(-/-) smooth muscle cells in vitro, revealed increased mRNA levels for procollagen alpha1(I) and alpha1(III) and tropoelastin, suggesting an enhancement of matrix synthesis in the absence of DDR1. Furthermore, whereas plaque smooth muscle cell content was unchanged, Ddr1(-/-);Ldlr(-/-) plaques had a 49% decrease in macrophage content at 12 weeks, with a concomitant reduction of in situ gelatinolytic activity. Moreover, mRNA expression of both monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 was reduced in vivo, and Ddr1(-/-);Ldlr(-/-) macrophages demonstrated impaired matrix metalloproteinase expression in vitro. These data suggest novel roles for DDR1 in macrophage recruitment and invasion during atherogenesis. In conclusion, our data support a role for DDR1 in the regulation of both inflammation and fibrosis early in plaque development. Deletion of DDR1 attenuated atherogenesis and resulted in the formation of matrix-rich plaques.

journal_name

Circ Res

journal_title

Circulation research

authors

Franco C,Hou G,Ahmad PJ,Fu EY,Koh L,Vogel WF,Bendeck MP

doi

10.1161/CIRCRESAHA.107.170662

subject

Has Abstract

pub_date

2008-05-23 00:00:00

pages

1202-11

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.107.170662

journal_volume

102

pub_type

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Discoidin domain receptor 1 (ddr1) deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice.