Gremlin-1 Is an Inhibitor of Macrophage Migration Inhibitory Factor and Attenuates Atherosclerotic Plaque Growth in ApoE−/− Mice

Abstract

Results:Gremlin-1 binds with high affinity to macrophage migration inhibitory factor and attenuates the progression of atherosclerosis. Conclusion:We describe a novel mechanism that regulates foam cell formation and plaque growth. Significance: The findings disclose a new mechanism for the regulation of plaque growth and may open novel therapeutic strategies to control the progression of atherosclerosis.Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/ Drm is crucial in embryo-/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin-1 in atherosclerosis. Here we report that Gremlin-1 is highly expressed primarily by monocytes/macrophages in aortic atherosclerotic lesions of ApoE Atherosclerosis is a chronic disease of the arteries characterized by inflammation of the vessel wall (1-3). Endothelial activation, monocyte recruitment, and the formation of macrophages are critical events in the development of atherosclerosis (4). Macrophages secrete cytokines/chemokines and growth factors that promote atheroprogression and contribute substantially to plaque vulnerability and acute complications of the disease such as acute coronary syndromes (5). The cytokine macrophage migration inhibitory factor (MIF) 2 is a noncognate ligand of CXC chemokine receptors and regulates monocyte recruitment toward atherosclerotic lesions (6). Blocking or genetic deletion of MIF reduces macrophage and T-cell content of atherosclerotic plaques and attenuates the progression of atherosclerosis in ApoE Ϫ/Ϫ mice (7). Gremlin-1 and its rat homolog Drm (down-regulated by v-mos) are highly conserved 20.7-kDa glycoproteins (8, 9). Gremlin-1 belongs to the DAN/Cerberus protein family, which is a member of the cysteine knot superfamily that includes TGF-␤ and VEGF (10). Gremlin-1 is a bone morphogenetic protein (BMP) antagonist and binds to BMP-2, -4, and -7 (9). It exists in secreted and cell-associated forms (9). The Gremlin-1 gene encodes a 23-and 28-kDa protein that is glycosylated before secretion (9). Gremlin-1-dependent inhibition of BMPs is important for embryogenesis and development of organs such as limbs, kidney, and lungs (11, 12). Gremlin-1 knock-out mice are neonatally lethal with significant renal and lung defects (13). Transgenic mice overexpressing Gremlin-1 under the control of the osteocalcin promoter show reduced bone formation (14). Gremlin-1 is expressed in endothelial cells exposed to disturbed flow in mouse aorta and in human coro-

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

“…54 Indeed, gremlin haplodeficiency reduces vascular remodeling in hypoxic lung and diabetes mellitus-associated kidney damage. 55 However, gremlin attenuates atherosclerotic plaque growth in ApoE − / − mice 56 and may act as neuroprotective factor for dopamine neuron degeneration. 57 Thus, the biological impact of gremlin downregulation or of its overexpression in different pathological settings seems to be strictly contextual.…”

Chemokines in Atherosclerosis

“…28 Recently, the structural requirements of MIF to bind to CXCR2 were addressed, and it was revealed that MIF-chemokine receptor interactions are dependent on a pseudo-(E)LR motif and an N-loop-based 2-site binding mechanisms, typical for bona fide chemokines. 48,49 Notably, Gremlin-1 was recently identified as an endogenous inhibitor of MIF, and administration of a recombinant fusion molecule mGremlin-1-Fc that binds to MIF substantially reduced atherosclerotic lesion formation, 50 indicating its potential as a novel therapeutic strategy to limit atheroprogression.…”

“…74 Moreover, the MIF inhibitor Gremlin-1 was shown to reduce atherosclerotic lesion formation. 50 Although a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies for inflammatory diseases are currently in clinical trials, only few molecules targeting chemokines and their receptors have been approved by the US Food and Drug Administration. 75,76 In 2007, the CCR5 inhibitor maraviroc (for prevention of HIV) was approved; the CXCR4 antagonist mozobil (for hematopoietic stem cell mobilization) was approved in 2008.…”

Macrophage Migration Inhibitory Factor Limits Activation-Induced Apoptosis of Platelets via CXCR7-Dependent Akt Signaling

“…[11][12][13][14][15] Because most of these diseases are ameliorated by either genetic deletion of Mif or MIF neutralization, anti-MIF therapies have raised significant clinical interest. MIF levels in plasma are enhanced in patients with acute myocardial infarction and associated with inflammatory markers C-reactive protein and IL-6 and correlate with cardiac necrosis marker troponin I release.…”