Objective-Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-␣ (TNF-␣), a cytokine identified to have a pathogenic role in chronic inflammatory diseases such as rheumatoid arthritis (RA). The aim of the study was to evaluate the importance of TNF-␣ in atherogenesis. Methods and Results-Mice deficient in both apolipoprotein E (apoE) and TNF-␣ were compared regarding their atherosclerotic burden. Mice were fed a Western-style diet (WD) or normal chow. Mice deficient in both apoE and TNF-␣ exhibited a 50% (Pϭ0.035) reduction of relative lesion size after 10 weeks of WD. Bone marrow transplantation of apoE o mice with apoE o tnf-␣ o bone marrow resulted in a 83% (Pϭ0.021) reduction after 25 weeks on WD. In apoE knockout mice treated with recombinant soluble TNF receptor I releasing pellets, there was a reduction in relative lesion size after 25 weeks of 75% (Pϭ0.018).Conclusions-These findings demonstrate that TNF-␣ is actively involved in the progression of atherosclerosis.Accordingly, TNF-␣ represents a possible target for prevention of atherosclerosis. This may be of particular importance in rheumatoid arthritis because these patients have an increased risk for cardiovascular disease.
Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion.
PRELP (proline arginine-rich end leucine-rich repeat protein) is a heparin-binding leucine-rich repeat protein in connective tissue extracellular matrix. In search of natural ligands and biological functions of this molecule, we found that PRELP binds the basement membrane heparan sulfate proteoglycan perlecan. Also, recombinant perlecan domains I and V carrying heparan sulfate bound PRELP, whereas other domains without glycosaminoglycan substitution did not. Heparin, but not chondroitin sulfate, inhibited the interactions. Glycosaminoglycanfree recombinant perlecan domain V and mutated domain I did not bind PRELP. The dissociation constants of the PRELP-perlecan interactions were in the range of 3-18 nM as determined by surface plasmon resonance. As expected, truncated PRELP, without the heparin-binding domain, did not bind perlecan. Confocal immunohistochemistry showed that PRELP outlines basement membranes with a location adjacent to perlecan. We also found that PRELP binds collagen type I and type II through its leucine-rich repeat domain. Electron microscopy visualized a complex with PRELP binding simultaneously to the triple helical region of procollagen I and the heparan sulfate chains of perlecan. Based on the location of PRELP and its interaction with perlecan heparan sulfate chains and collagen, we propose a function of PRELP as a molecule anchoring basement membranes to the underlying connective tissue.
We have determined the primary structure of a connective tissue matrix protein from the nucleotide sequence of a clone isolated from a human articular chondrocyte cDNA library. The major part of the amino acid sequence has also been determined by direct protein sequencing. The translated primary sequence corresponds to 382 amino acid residues, including a 20-residue signal peptide. The molecular mass of the mature protein is 41,646 Da. The main part of the protein consists of 10 leucine-rich repeats ranging in length from 20 to 26 residues, with asparagine at position 10 (B-type). The N-terminal part is unusual in that it is basic and rich in arginine and proline. There are four potential N-linked glycosylation sites present. In three of these sites, post-translational modifications are likely to be present since Asn was not found by direct protein sequencing. The amino-and carboxyl-terminal parts contain four and two cysteine residues, respectively, probably forming disulfide bonds by analogy with the other members of this family. The protein shows highest identity (36%) to fibromodulin and 33% to bovine lumican, two other leucine-rich repeat connective tissue proteins. Northern blot analysis showed the presence of an ϳ3.8-kilobase mRNA in different types of bovine cartilage and cultured osteoblasts, whereas RNAs isolated from bovine kidney, skin, spleen, thymus, and trabecular bone and rat calvaria were negative. Human articular chondrocyte and rat chondrosarcoma cell RNAs contained an additional mRNA of ϳ1.6 and 1.8 kilobases, respectively. Connective tissues are dominated by an extensive extracellular matrix. In cartilage, the matrix has an abundance of collagen II and aggrecan, the large aggregating proteoglycan. The extracellular matrix is also rich in smaller proteoglycans and other non-collagenous proteins. A few years ago, it was shown that one of the first sequenced smaller proteoglycans, decorin (1, 2), contains leucine-rich repeats (LRRs).1 Since then, the number of identified primary sequences for LRR proteins in connective tissues has increased. Connective tissue proteins of the extracellular matrix with LRRs so far known are biglycan (3), decorin and fibromodulin (4), lumican (5), chondroadherin (6), proteoglycan-Lb (7), and osteoinductive factor (8).Except for chondroadherin, all of them are proteoglycans with one or a few glycosaminoglycan chains, and several of these molecules have been shown to bind components of the extracellular matrix, e.g. collagen (9), growth factors (10), and cells (11). Intra-and extracellular LRR-containing proteins are found in almost any system studied, e.g. in mammalian and plant cells, yeast, and prokaryotes (12). The number of residues in a given LRR is between 20 and 29, and the consensus sequence derived from all known LRR proteins contains leucine or other aliphatic residues at positions 2, 5, 7, 12, 16, 21, and 24 and asparagine (B-type repeat), cysteine (A-type repeat), or threonine at position 10. Recently, the three dimensional structure of the LRR-containi...
Inactivation of the perlecan gene leads to perinatal lethal chondrodysplasia. The similarity to the phenotypes of the Col2A1 knock-out and the disproportionate micromelia mutation suggests perlecan involvement in cartilage collagen matrix assembly. We now present a mechanism for the defect in collagen type II fibril assembly by perlecan-null chondrocytes. Cartilage perlecan is a heparin sulfate or a mixed heparan sulfate/chondroitin sulfate proteoglycan. The latter form binds collagen and accelerates fibril formation in vitro, with more defined fibril morphology and increased fibril diameters produced in the presence of perlecan. Interestingly, the enhancement of collagen fibril formation is independent on the core protein and is mimicked by chondroitin sulfate E but neither by chondroitin sulfate D nor dextran sulfate. Furthermore, perlecan chondroitin sulfate contains the 4,6-disulfated disaccharides typical for chondroitin sulfate E. Indeed, purified glycosaminoglycans from perlecan-enriched fractions of cartilage extracts contain elevated levels of 4,6-disulfated chondroitin sulfate disaccharides and enhance collagen fibril formation. The effect on collagen assembly is proportional to the content of the 4,6-disulfated disaccharide in the different cartilage extracts, with growth plate cartilage glycosaminoglycan being the most efficient enhancer. These findings demonstrate a role for perlecan chondroitin sulfate side chains in cartilage extracellular matrix assembly and provide an explanation for the perlecan-null chondrodysplasia.
Objective— Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Approach and Results— Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. Conclusions— The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.
AimsIdentification and treatment of the rupture prone atherosclerotic plaque remains a challenge for reducing the burden of cardiovascular disease. The interconnection of metabolic and inflammatory processes in rupture prone plaques is poorly understood. Herein, we investigate associations between metabolite profiles, inflammatory mediators and vulnerability in carotid atherosclerotic plaques.Methods and resultsWe collected 159 carotid plaques from patients undergoing endarterectomy and measured 165 different metabolites in a targeted metabolomics approach. We identified a metabolite profile in carotid plaques that associated with histologically evaluated vulnerability and inflammatory mediators, as well as presence of symptoms in patients. The distinct metabolite profiles identified in high-risk and stable plaques were in line with different transcription levels of metabolic enzymes in the two groups, suggesting an altered metabolism in high-risk plaques. The altered metabolic signature in high-risk plaques was consistent with a change to increased glycolysis, elevated amino acid utilization and decreased fatty acid oxidation, similar to what is found in activated leucocytes and cancer cells.ConclusionThese results highlight a possible key role of cellular metabolism to support inflammation and a high-risk phenotype of atherosclerotic plaques. Targeting the metabolism of atherosclerotic plaques with novel metabolic radiotracers or inhibitors might therefore be valid future approaches to identify and treat the high-risk atherosclerotic plaque.
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