Relative Biological Activity Research Articles

Human Chorionic Gonadotropin: A Model Molecule For Oligopeptide-Based Drug Discovery

Small degradation products of proteins can have regulatory powers in biological systems. We have studied the role of selected oligopeptides derived from the pregnancy hormone human chorionic gonadotropin (hCG) in several(patho)physiological systems. The employed oligopeptides (3 up to 7 amino acids) were designed according to the known nick sites in 'loop-2' of β-hCG. These oligopeptides can inhibit severe inflammation, the onset of type I diabetes, renal failure and tumorigenesis. One of the oligopeptides (AQGV) appeared capable of accelerating recuperation after lethal radiation of mice, thereby reducing the number of deaths among the irradiated mice. This particular oligopeptide has already been successfully tested in human Phase I and IIa studies. Regulating oligopeptides are not only released as a specific subset by degradation of the pregnancy hormone hCG, but also during the degradation of other body proteins and possibly also by transcription of so-called 'non-coding' mRNA. Based on a system's biology approach we designed a series of oligopeptides with particular physico-chemical properties based on the primary structure of β-catenin and C-reactive protein (CRP). Several of the designed oligopeptides were able to inhibit vital genes involved in cell division in a plant model. We call such oligopeptides with regulating activity 'peptide-i' peptides, referring to their ability to interfere with the expression of particular genes, and thus with the expression of the related biological activities. The fact that the selected oligopeptides can inhibit the multiplication of plant cells suggests that these peptides, through evolution, are part of a hitherto unknown conserved regulatory system. Based on the data presented we foresee the development of many new regulatory oligopeptide-based pharmaceuticals, which could be a serious option for addressing new therapeutic challenges.

Structure Based Virtual Inhibitor Screening of Membrane Channel Proteins

In the context of computer aided drug design we validated, optimized and applied methods for the estimation of absolute and relative biological activities of drug like molecules acting on membrane channel proteins. These proteins are important for many different physiological processes and therefore attractive targets for modern drug discovery. Structure Based Virtual Screening (SBVS) is an established technique in drug design, but it is still unclear whether standard SBVS approaches can be successfully applied to channel like proteins. Based on a library of 2675 compounds with known activity on the voltage gated potassium channel Kv1.2, the ability to identify active and inactive compounds of three different Structure Based Virtual Screening algorithms were evaluated. We found that the approaches cannot be applied to cavity like active sites without further ado. The algorithms were optimized and combined by consensus approaches. These approaches were applied to the clean-drug-like subset of the ZINC database and validated by electrophysiological experiments.

The Zwitterionic Cell Wall Teichoic Acid of Staphylococcus aureus Provokes Skin Abscesses in Mice by a Novel CD4+ T-Cell-Dependent Mechanism

Zwitterionic polysaccharide (ZPS) components of the bacterial cell envelope have been shown to exert a major histocompatibility complex (MHC) II-dependent activation of CD4+ T cells, which in turn can modulate the outcome and progression of infections in animal models. We investigated the impact of zwitterionic cell wall teichoic acid (WTA) produced by Staphylococcus aureus on the development of skin abscesses in a mouse model. We also compared the relative biological activities of WTA and capsular polysaccharide (CP), important S. aureus pathogenicity factors, in abscess formation. Expression of both WTA and CP markedly affected the ability of S. aureus to induce skin abscess formation in mice. Purified wild-type zwitterionic WTA was more active in inducing abscess formation than negatively charged mutant WTA or purified CP8. To assess the ability of purified native WTA to stimulate T cell proliferation in vitro, we co-cultivated WTA with human T-cells and antigen presenting cells in the presence and absence of various inhibitors of MHC-II presentation. Wild-type WTA induced T cell proliferation to a significantly greater extent than negatively charged WTA. T cell activation was dependent on the presentation of WTA on MHC II, since inhibitors of MHC II-dependent presentation and antibodies to MHC II significantly reduced T cell proliferation. T cells activated in vitro with wild-type WTA, but not negatively charged WTA, induced abscess formation when injected subcutaneously into wild-type mice. CD4−/− mice similarly injected with WTA failed to develop abscesses. Our results demonstrate that the zwitterionic WTA of S. aureus induces CD4+ T-cell proliferation in an MHCII-dependent manner, which in turn modulates abscess formation in a mouse skin infection model. An understanding of this novel T cell-dependent host response to staphylococcal abscess formation may lead to the development of new strategies to combat S. aureus skin and soft tissue infections.

ChemInform Abstract: Synthesis, Biological Activity and Metabolism of N-Hydroxytryptophan.

Abstract N -Hydroxytryptophan (α-hydroxyamino-β-indolyl-3-propionic acid) was chemically synthesized. On a mole basis, its relative biological activity in comparison with indole-3-acetic acid at sub-optimal concentrations is: oat coleoptile curvature test=0.129; oat first internode test=0.089 and linseed root growth inhibition test=0.022. Infiltration of N -hydroxytryptophan into oat coleoptile sections leads to the production of indoleacetaldehyde oxime, indoleacetaldehyde and indoleacetic acid. It is suggested that tryptophan could be metabolized in oat coleoptiles to indole-3-acetic acid via N -hydroxytryptophan, indoleacetaldehyde oxime and indoleacetaldehyde.

Trypanosoma brucei Modifies the Tsetse Salivary Composition, Altering the Fly Feeding Behavior That Favors Parasite Transmission

Tsetse flies are the notorious transmitters of African trypanosomiasis, a disease caused by the Trypanosoma parasite that affects humans and livestock on the African continent. Metacyclic infection rates in natural tsetse populations with Trypanosoma brucei, including the two human-pathogenic subspecies, are very low, even in epidemic situations. Therefore, the infected fly/host contact frequency is a key determinant of the transmission dynamics. As an obligate blood feeder, tsetse flies rely on their complex salivary potion to inhibit host haemostatic reactions ensuring an efficient feeding. The results of this experimental study suggest that the parasite might promote its transmission through manipulation of the tsetse feeding behavior by modifying the saliva composition. Indeed, salivary gland Trypanosoma brucei-infected flies display a significantly prolonged feeding time, thereby enhancing the likelihood of infecting multiple hosts during the process of a single blood meal cycle. Comparison of the two major anti-haemostatic activities i.e. anti-platelet aggregation and anti-coagulation activity in these flies versus non-infected tsetse flies demonstrates a significant suppression of these activities as a result of the trypanosome-infection status. This effect was mainly related to the parasite-induced reduction in salivary gland gene transcription, resulting in a strong decrease in protein content and related biological activities. Additionally, the anti-thrombin activity and inhibition of thrombin-induced coagulation was even more severely hampered as a result of the trypanosome infection. Indeed, while naive tsetse saliva strongly inhibited human thrombin activity and thrombin-induced blood coagulation, saliva from T. brucei-infected flies showed a significantly enhanced thrombinase activity resulting in a far less potent anti-coagulation activity. These data clearly provide evidence for a trypanosome-mediated modification of the tsetse salivary composition that results in a drastically reduced anti-haemostatic potential and a hampered feeding performance which could lead to an increase of the vector/host contact and parasite transmission in field conditions.

Random molecular substructures as fragment-type descriptors

A novel approach for analysis of structure-activity relationships for sets of active compounds is reported. Molecular similarity relationships are analyzed among compounds with related biological activity based on the evaluation of randomly generated fragment populations. Fragments are randomly generated by iterative bond deletion in molecular graphs and hence depart from those obtained by well-defined fragmentation schemes [1]. A major finding has been that for any given activity class, dependency relationships of fragment co-occurrence exists within random fragment populations. Through the analysis of these relationships the chemical information content of generated substructures can be quantified [2]. This has lead to the identification of small numbers (10- 40) of so-called activity class characteristic substructures (ACCS) that have been successfully utilized in virtual screening applications [3,4].

Diversified cardiovascular actions of six homologous natriuretic peptides (ANP, BNP, VNP, CNP1, CNP3, and CNP4) in conscious eels

The natriuretic peptide (NP) family consists of seven paralogs [atrial NP (ANP), brain NP (BNP), ventricular NP (VNP), and C-type NP 1-4 (CNP1-4)] in teleosts, but relative biological activity of the seven NPs has not been comprehensively examined using homologous peptides. In this study, we newly identified CNP3 and CNP4 in eels to use homologous peptides, but the CNP2 gene may have been silenced in this species. The CNP4 gene was expressed exclusively in the brain as CNP1, but the CNP3 gene, from which cardiac ANP, BNP, and VNP were generated by tandem duplication, was most abundantly expressed in the pituitary, suggesting its local action. All NPs induced hypotension dose dependently after intra-arterial injection with a potency order of ANP > VNP > BNP > CNP4 > CNP1 = CNP3. The degree of hypotension was similar at the ventral and dorsal aorta, indicating similar actions on the branchial and systemic circulation. The hypotension induced by cardiac NPs was longer lasting than CNPs, probably because of the difference in preferential receptors. Among cardiac NPs, the hypotensive effect of VNP lasted much longer than those of ANP and BNP, even though VNP disappeared from the blood more quickly than ANP. To analyze the unique effect of VNP, we examined possible involvement of the autonomic nervous system using ANP, VNP, and CNP3. Beta-adrenergic blockade diminished hypotensive effects of all three NPs, but alpha-adrenergic and cholinergic blockade enhanced only the effect of VNP, suggesting a specific mechanism for the VNP action. The NP-induced tachycardia was diminished by all blockers examined. Furthermore, the cardiovascular action of VNP was not impaired by a blocker of NP receptor, HS-142-1. Taken together, the homologous NPs exhibit diverse cardiovascular actions in eels partially through the autonomic nervous system, and the unique VNP action may be mediated by a novel receptor that has not been identified in teleosts.

Effects of Tunisian medicinal plant extracts on the expression of cell defense genes in human leukemia cell line K562 using cDNA arrays: Correlation with related biological activities

Effects of Tunisian medicinal plant extracts on the expression of cell defense genes in human leukemia cell line K562 using cDNA arrays: Correlation with related biological activities

Fragment Formal Concept Analysis Accurately Classifies Compounds with Closely Related Biological Activities

Fragment formal concept analysis (FragFCA) for compound classification: Signature fragment combinations for compound classes with closely related biological activity were identified using FragFCA. These combinations are used to accurately classify active test compounds on the basis of fragment mapping. FragFCA can extract class-specific fragment combinations from compounds active against different target families that have signature character and practical utility in compound classification and database searching.Formal concept analysis (FCA), originally developed in information science, has been adapted to identify relationships between fragments of compounds and their biological activity. Here applications of the FragFCA approach with practical utility for medicinal chemistry are explored. Hierarchically derived fragment populations of 24 classes of compounds active against eight target families were subjected to FragFCA analysis, and fragment combinations were identified that distinguished compounds with closely related biological activity from each other. Mapping of signature fragment combinations was carried out to classify active compounds for different target families with high accuracy. The results indicate that compound-class-specific structural information and selectivity determinants are predominantly encoded by fragment combinations, rather than individual fragments. Furthermore, class-specific fragment combinations were successfully applied in similarity searching. The results demonstrate that FragFCA is capable of identifying fragment combinations that differentiate between compound sets with closely related biological activity and that can be used to predict structure-activity relationships.

Predicting Protein Complexes from PPI Data: A Core-Attachment Approach

Protein complexes play a critical role in many biological processes. Identifying the component proteins in a protein complex is an important step in understanding the complex as well as the related biological activities. This paper addresses the problem of predicting protein complexes from the protein-protein interaction (PPI) network of one species using a computational approach. Most of the previous methods rely on the assumption that proteins within the same complex would have relatively more interactions. This translates into dense subgraphs in the PPI network. However, the existing software tools have limited success. Recently, Gavin et al. (2006) provided a detailed study on the organization of protein complexes and suggested that a complex consists of two parts: a core and an attachment. Based on this core-attachment concept, we developed a novel approach to identify complexes from the PPI network by identifying their cores and attachments separately. We evaluated the effectiveness of our proposed approach using three different datasets and compared the quality of our predicted complexes with three existing tools. The evaluation results show that we can predict many more complexes and with higher accuracy than these tools with an improvement of over 30%. To verify the cores we identified in each complex, we compared our cores with the mediators produced by Andreopoulos et al. (2007), which were claimed to be the cores, based on the benchmark result produced by Gavin et al. (2006). We found that the cores we produced are of much higher quality ranging from 10- to 30-fold more correctly predicted cores and with better accuracy. (http://alse.cs.hku.hk/complexes/).

Gene frequency and partial protein characterization of an allelic variant of mannan binding protein associated with low serum concentrations.

Low plasma concentration of mannan binding protein (MBP) has been shown to be the basis for a common opsonic deficiency and suggested to be caused by a single nucleotide substitution at base 230 of exon 1 in the MBP gene. This substitution causes a replacement of glycine (codon GGC) with aspartic acid (codon GAC). Of 123 healthy Danish individuals investigated by polymerase chain reaction performed on exon 1, followed by restriction fragment length polymorphism or allospecific probing, 93 were homozygous (75.6%) for GGC, 28 heterozygous (22.8%), and two homozygous for GAC (1.6%). The gene frequency of the GAC allele was found to be 0.13. DNA sequencing of the cloned exon 1 from one GAC homozygous individual revealed no other substitution. The median MBP concentration in the group containing the GAC allele was 6.4 times lower than in the GGC homozygous group (195 and 1234 micrograms/l respectively). However, the range in plasma concentrations of MBP was wide and overlapping between the groups. MBP protein was detected in both the GAC homozygotes (9 and 387 micrograms/l). Furthermore, no difference in relative mass and biological activity (mannan binding) was found when sera containing the two forms of MBP were investigated. Accordingly, it can be concluded that the GAC allele is able to produce a functional MBP protein which may be detected in serum at low concentrations.

Highly Crosslinked vs Conventional Polyethylene Particles—An In Vitro Comparison of Biologic Activities

Highly cross-linked polyethylenes (HXPEs) have been introduced to reduce wear after hip arthroplasty. The improved wear characteristics of HXPEs are well documented, but the relative biologic activity of HXPE and conventional polyethylene (CPE) particles remains unclear. Longevity (Zimmer, Warsaw, Ind; HXPE) and GUR 1050 (Zimmer; CPE) particles were isolated and characterized from a hip simulator and their in vitro inflammatory responses (tissue necrosis factor α, interleukin 1 α, and vascular endothelial growth factor levels) were compared using macrophages. The average diameter of Longevity particles (0.111 μm) was smaller than CPE particles (0.196 μm), and both were predominantly round (granular appearance). The inflammatory response to HXPE and CPE was concentration-dependent. No statistically significant differences were noted at low (0.1 surface area ratio [SAR]) and intermediate (0.75 SAR) doses. At the highest dose tested (2.5 SAR), HXPE was significantly more inflammatory than CPE based on relative tissue necrosis factor α and vascular endothelial growth factor secretion levels. Further study is needed to determine if similar findings would be noted in vivo over a broad concentration range.

Synthesis and Biological Evaluation of Amide Derivatives of (6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic Acid as Potential Anti-inflammatory Agents with Lower Gastrointestinal Toxicity

A variety of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid were synthesized and screened for their anti-inflammatory and related biological activities. These compounds were found to be longer acting and showed residual activity exceeding that of standard indomethacin. The studies with SKF-525A, a standard hepatic microsomal enzyme inhibitor showed that probably the test compound per se is the active species. The compound 6y showed best activity profile with ED30 of 6.45 mg/kg however this compound was found to be toxic at 100 mg/kg p.o. Though these compounds exhibited appreciable analgesic and antipyretic activities but they failed to prevent the development of secondary inflammation in adjuvant induced arthritis assay. The compound 6x showed 94% inhibition of acetic acid induced writhing. Studies showed that antagonism of TNF-alpha is not possibly involved in the mechanism of action of these compounds. However these compounds were found to have only mild ulcerogenic potential at the tested dose level of 100 mg/kg p.o. in comparison to indomethacin.

Comparison between the free‐radical‐scavenging activities with vitamin E and ubiquinol in biological systems based on their reaction rates: A research account

Detailed kinetic studies have been performed for the reaction of aroxyl (ArO.) radical with vitamin E (alpha-, beta-, gamma-, delta-tocopherol, TocH), ubiquinol-10, and related antioxidants in micellar solution, using a stopped-flow spectrophotometer. The second-order reaction rates (ks) obtained increased in the order of hydroquinone < tocol<delta-TocH<ubiquinol-0<gamma-TocH-beta-TocH<ubiquinol-10<alpha-TocH at pH 4-8. The antioxidants which have lower oxidation potentials (Ep) showed higher reactivities. The reaction rates obtained in micellar solution were pH dependent because of the dissociation of OH groups in the antioxidants. For instance, by comparing the ks values with the mole fraction of each molecular form of ubiquinol-10, the reaction rate ks1 (1.21 x 10(5) M(-1)s(-1)) for undissociated form, ks2 (1.04 x 10(6) M(-1)s(-1)) for monoanion and ks3 (0 M(-1)s(-1)) for dianion, and the pKa1 and pKa2 values (11.4 and 12.7) were determined. It was found that the relative ratio of ks values (100:21:20:2.9) of alpha-, beta-, gamma-, delta-tocopherols in micellar dispersion has good correlation with the relative biological activities for rat fetal resorption, rat haemolysis, and chicken muscle dystrophy. The relative antioxidant activities of alpha-tocopherol and ubiquinol-10 have been discussed on the basis of the products of the ks values and their concentrations in serum and several tissues (heart, muscle, liver, kidney, and brain).

Analytical aspects of pharmaceutical grade chondroitin sulfates

Chondroitin sulfate is a very heterogeneous polysaccharide in terms of relative molecular mass, charge density, chemical properties, biological and pharmacological activities. It is actually recommended by EULAR as a symptomatic slow acting drug (SYSADOA) in Europe in the treatment of knee osteoarthritis based on meta-analysis of numerous clinical studies. Chondroitin sulfate is also utilized as a nutraceutical in dietary supplements mainly in the United States. On the other hand, chondroitin sulfate is derived from animal sources by extraction and purification processes. As a consequence, source material, manufacturing processes, the presence of contaminants, and many other factors contribute to the overall biological and pharmacological actions of these agents. The aim of this review is to evaluate new possible more specific analytical approaches to the determination of the origin and purity of chondroitin sulfate preparations for pharmaceutical application and in nutraceuticals, such as the evaluation of the molecular mass values, the constituent disaccharides, and the specific and sensitive agarose-gel electrophoresis technique. Furthermore, a critical evaluation is presented, together with a discussion of the limits of these analytical approaches. Finally, the necessity for reference standards having high specificity, purity and well-known physico-chemical properties useful for accurate and reproducible quantitative analyses will be discussed.

Bone-like matrix formation on magnesium and magnesium alloys

Mg metal and its alloys have promise as a biocompatible, degradable biomaterials. This work evaluates the potential of in vitro cell culture work with osteoblast-like cells on Mg based materials, and investigates cell differentiation and growth on Mg alloyed with various non-toxic or low-toxicity elements. Mg based substrates support the adhesion, differentiation and growth of stromal cells towards an osteoblast-like phenotype with the subsequent production of a bone like matrix under in vitro conditions. No significant difference in the final tissue layer is observed on pure Mg, an AZ21 alloy or a 0.5 wt% Ca alloy. Only a 0.8 wt% Ca alloy which shows complete structural disintegration shows minimal cell growth. Due to association of non-soluble degradation products formed when Mg is incubated in physiological-like fluid, mass changes typically used to report Mg degradation are not viable estimates of degradation. Methods quantifying the time dependent change in the mechanical integrity of samples as a function of incubation time are required for a proper assessment of Mg degradation. We conclude that in vitro cell culture of bone cells on Mg substrates is expected to be a viable screening technique to assess the relative biological activity of Mg-based materials.

Molecular and Cellular Activities of Vitamin E Analogues

Natural vitamin E comprises 8 different analogues, the alpha-, beta-, gamma-, and delta-tocopherols and the alpha-, beta-, gamma-, and delta-tocotrienols. However, only alpha-tocopherol is selectively enriched by the liver; the other vitamin E analogues and also excess alpha-tocopherol are converted to several metabolites and eliminated. Recently, a novel phosphorylated form of tocopherol, alpha-tocopheryl phosphate, was shown to occur naturally in animal and human tissues as well as in foods. Several synthetic vitamin E derivatives have been synthesized that are either converted by esterases to the natural form, or exert novel or vitamin E related biological activities. During the last years, specific cellular effects for each individual vitamin E analogue have been described that are the consequence of modulating signal transduction and gene expression. These effects possibly reflect specific interactions of each of the vitamin E analogues with enzymes, structural proteins, lipids and transcription factors. In this review, the different natural vitamin E analogues and synthetic derivatives are compiled in relation to their major molecular and cellular activities.

Characterization of two brassinosteroid C-6 oxidase genes in pea.

C-6 oxidation genes play a key role in the regulation of biologically active brassinosteroid (BR) levels in the plant. They control BR activation, which involves the C-6 oxidation of 6-deoxocastasterone (6-DeoxoCS) to castasterone (CS) and in some cases the further conversion of CS to brassinolide (BL). C-6 oxidation is controlled by the CYP85A family of cytochrome P450s, and to date, two CYP85As have been isolated in tomato (Solanum lycopersicum), two in Arabidopsis (Arabidopsis thaliana), one in rice (Oryza sativa), and one in grape (Vitis vinifera). We have now isolated two CYP85As (CYP85A1 and CYP85A6) from pea (Pisum sativum). However, unlike Arabidopsis and tomato, which both contain one BR C-6 oxidase that converts 6-DeoxoCS to CS and one BR C-6 Baeyer-Villiger oxidase that converts 6-DeoxoCS right through to BL, the two BR C-6 oxidases in pea both act principally to convert 6-DeoxoCS to CS. The isolation of these two BR C-6 oxidation genes in pea highlights the species-specific differences associated with C-6 oxidation. In addition, we have isolated a novel BR-deficient mutant, lke, which blocks the function of one of these two BR C-6 oxidases (CYP85A6). The lke mutant exhibits a phenotype intermediate between wild-type plants and previously characterized pea BR mutants (lk, lka, and lkb) and contains reduced levels of CS and increased levels of 6-DeoxoCS. To date, lke is the only mutant identified in pea that blocks the latter steps of BR biosynthesis and it will therefore provide an excellent tool to further examine the regulation of BR biosynthesis and the relative biological activities of CS and BL in pea.

Modeling Clinically Heterogeneous Presenilin Mutations with Transgenic Drosophila

To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years . PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity . Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease.

Novel Transgenic Rabbit Model Sheds Light on the Puzzling Role of Matrix Metalloproteinase-12 in Atherosclerosis

Matrix metalloproteinases (MMPs), also termed matrixins, are known to affect atherosclerosis in many diverse ways.1–3 Apart from a role in the progression of atherosclerotic lesions, MMPs have also been involved in plaque destabilization and rupture and in the development of aneurysms. Despite intense research efforts during the last decade, it has been challenging to formulate a unifying model on the specific role of MMPs in atherosclerosis. In fact, mouse genetic studies have yielded controversial insights, highly dependent on genetic background, dietary regimen, and arterial site of analysis, whereas human genetic association studies do not prove causality of MMPs in atherosclerosis. Moreover, the lack of specific inhibitors precluded pharmacological dissection of the role of MMPs in vivo. There is thus a need for alternative strategies to decipher the MMP puzzle in atherosclerosis. In this issue of Circulation , Liang et al4 used a novel approach: They generated transgenic rabbits to study the role of MMP-12, also known as macrophage elastase, in atherosclerosis. Their results indicate that MMP-12 causes media destruction and pseudoaneurysm formation and, more surprisingly, accelerates plaque growth in an animal model that more closely resembles atherosclerosis in humans. Article p 1993 MMPs belong to one of the most ancient families of enzymes that arose in evolution soon after the first signs of life to regulate, in general, interactions of cells with the extracellular matrix (ECM). To cope with this formidable challenge, more than 65 structurally related MMPs developed in bacteria, plants, nematodes, fruit flies, sea urchins, and vertebrates. One of their key activities is breaking down ECM substrates in the basement membrane and interstitial matrix.1,2 As such, MMPs facilitate migration of macrophages and smooth muscle cells (SMCs) in atherosclerotic plaques by degrading ECM barriers, exposing novel ECM adhesion sites, and relieving the binding between basement membrane …