Discoidin Domain Receptor 1 ( Ddr1 ) Deletion Decreases Atherosclerosis by Accelerating Matrix Accumulation and Reducing Inflammation in Low-Density Lipoprotein Receptor–Deficient Mice

Abstract

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 ϩ/ϩ ;Ldlr Ϫ/Ϫ and Ddr1 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ 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 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ plaques exhibited accelerated deposition of fibrillar collagen and elastin at 12 weeks compared with Ddr1 ϩ/ϩ ;Ldlr Ϫ/Ϫ plaques. Expression analysis of laser microdissected lesions in vivo, and of Ddr1 Ϫ/Ϫ smooth muscle cells in vitro, revealed increased mRNA levels for procollagen ␣1(I) and ␣1(III) and tropoelastin, suggesting an enhancement of matrix synthesis in the absence of DDR1. Furthermore, whereas plaque smooth muscle cell content was unchanged, Ddr1 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ 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 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ 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. Key Words: atherosclerosis Ⅲ discoidin domain receptor 1 Ⅲ collagen Ⅲ inflammation Ⅲ macrophage A therosclerosis is a fibroinflammatory disease of the arterial wall. The atherosclerotic plaque is home to multiple cell types, including endothelial cells, smooth muscle cells (SMCs), and bone marrow-derived monocyte/ macrophages, all interacting within a chronically inflamed, lipid-rich, and highly dynamic extracellular matrix microenvironment. Collagens are critical components of the extracellular matrix present within atherosclerotic plaques, where they contribute to lesion volume and can constitute up to 60% of total plaque protein. 1 Collagens also provide mechanical stability to the fibrous cap and protect against plaque rupture, a major cause of the clinical complications associated with atherosclerosis. 2 Furthermore, collagens stimulate diverse cellular responses that are central to plaque development. For example, collagen synthesis and degradation are important for smooth muscle cell migration, 3,4 and degraded type I collagen fragments stimulate the disassembly of focal adhesion complexes in SMCs. 5 By contrast, intact type I collagen inhibits SMC proliferation. 6 Additionally, type I collagen promotes monocyte differentiation ...

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

“…4 -6 A number of studies have shown that DDR1 is implicated in carcinogenesis, inflammation, atherosclerosis, and fibrogenesis. [7][8][9][10][11][12] Consistent with an important pathogenetic role in vascular diseases, 8,[13][14][15] we have demonstrated that DDR1-deficient mice were protected against renal vascular lesions induced by a long-term infusion of angiotensin II, a model in which hemodynamic alterations and vascular remodeling play a major role. 11 Whether DDR1 may contribute to the initiating mechanisms and the progression of renal fibrosis irrespective of the initial cause remains unclear.…”

“…Such a protective effect of DDR1 deletion secondary to its antiinflammatory effect has been also demonstrated in a model of atherosclerosis in mice. 8 Moreover, Gross et al 25 recently studied the role of DDR1 in the kidney of Col4A3-deficient mice and suggested that podocyte-matrix interactions via DDR1 may play a role in glomerular injury in Alport syndrome. DDR1 deficiency was also associated with reduced inflammation in the latter study.…”

“…26 However, alternative factors, including DDR1 expression in resident cells, may also be directly involved in ECM deposition in this setting. Recent in vivo studies on smooth muscle cells 8,35 and in vitro 7,24 results have demonstrated that DDR1 activation resulted in a decrease of matrix accumulation and fibrillogenesis. The effect of DDR1 on matrix production may depend on the cell type and the environment.…”

Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML

“…Notably, a DDR1 knock-out is associated with increased plaque formation in murine arteriosclerosis models [30][31][32]. On the other hand, as mentioned above, DDR1 is also a target of imatinib and depending on the model analyzed, DDR1-inhibition has even been reported to protect from arterioslerosis [33].…”

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

“…That such an approach is feasible has been borne out in studies in which blockage of T cells reactive to native lipoprotein ApoB100 (4) or mucosal or subcutaneous immunization with HSP65 (9, 10), oxidized LDL (11), native ␤2-glycoprotein I (12), or apolipoprotein B-100 peptide (13,14) have been shown to be atheroprotective. Collagens can compose up to 60% of the total protein content in atherosclerotic plaques (15) and stimulate the growth and inflammation of atheromas (16). We have shown previously that interleukin 17-dependent autoimmunity to type V collagen col(V)) is a consistent feature of atherosclerosis in advanced CAD in humans and in Apoe Ϫ/Ϫ mice on a high-fat diet (17).…”