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Cardiovascular Research Aug 2023Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such...
AIMS
Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis.
METHODS AND RESULTS
The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding, rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30% reduction in E/e' and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a down-regulation of transforming growth factor (TGF)-β target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-β levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent-binding protein of TGF-β and extra domain A-fibronectin. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity.
CONCLUSION
Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction.
Topics: Rats; Humans; Animals; Disintegrins; Myocardium; Heart Failure; Cardiomyopathies; Collagen; Fibroblasts; Transforming Growth Factor beta; Thrombospondins; Metalloproteases; Fibrosis
PubMed: 37216909
DOI: 10.1093/cvr/cvad078 -
The FEBS Journal Jun 2023CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand...
CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand CD95L induces its oligomerization leading in turn to the transduction of either apoptotic or nonapoptotic signals. CD95L can exist as both membrane-anchored and soluble forms (sCD95L), the latter resulting from the proteolytic cleavage of the former. Candidate proteases able to achieve CD95L cleavage were identified as matrix metalloproteases (MMP) due to their demonstrated ability to cleave other TNF superfamily ligands. The main goal of this study was to systematically identify the MMP family members capable of cleaving CD95L and subsequently determine the corresponding cleavage sites. By using different orthogonal biochemical approaches and combining them with molecular modelling, we confirmed data from the literature regarding CD95L cleavage by MMP-3 and MMP-7. Moreover, we found that MMP-2 and MMP-12 can cleave CD95L and characterized their resulting cleavage sites. This study provides a systematic approach to analyse the cleavage of CD95L, which until now had only been poorly described.
Topics: Fas Ligand Protein; fas Receptor; Metalloproteases; Apoptosis
PubMed: 36694998
DOI: 10.1111/febs.16737 -
Toxins Jul 2018Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A⁻G). The Centers for Disease... (Review)
Review
Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A⁻G). The Centers for Disease Control classifies BoNTs as 'Category A' select agents and are the most lethal protein toxins for humans. Recently, BoNT-like proteins have also been identified in several non-clostridia. BoNTs are di-chain proteins comprised of an -terminal zinc metalloprotease Light Chain (LC) and a C-terminal Heavy Chain (HC) which includes the translocation and receptor binding domains. The two chains are held together by a disulfide bond. The LC cleaves Soluble -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The cleavage of SNAREs inhibits the fusion of synaptic vesicles to the cell membrane and the subsequent release of acetylcholine, which results in flaccid paralysis. The LC controls the catalytic properties and the duration of BoNT action. This review discusses the mechanism for LC catalysis, LC translocation, and the basis for the duration of LC action. Understanding these properties of the LC may expand the applications of BoNT as human therapies.
Topics: Animals; Botulinum Toxins; Humans; Neurotoxins; SNARE Proteins
PubMed: 30004421
DOI: 10.3390/toxins10070268 -
World Journal of Microbiology &... May 2018Vibrio parahaemolyticus, a Gram-negative bacterium, inhabits marine and estuarine environments and it is a major pathogen responsible globally for most cases of... (Review)
Review
Vibrio parahaemolyticus, a Gram-negative bacterium, inhabits marine and estuarine environments and it is a major pathogen responsible globally for most cases of seafood-associated gastroenteritis in humans and acute hepatopancreatic necrosis syndrome in shrimps. There has been a dramatic worldwide increase in V. parahaemolyticus infections over the last two decades. The pathogenicity of V. parahaemolyticus has been linked to the expression of different kinds of virulence factors including extracellular proteases, such as metalloproteases and serine proteases. V. parahaemolyticus expresses the metalloproteases; PrtV, VppC, VPM and the serine proteases; VPP1/Protease A, VpSP37, PrtA. Extracellular proteases have been identified as potential virulence factors which directly digest many kinds of host proteins or indirectly are involved in the processing of other toxic protein factors. This review summarizes findings on the metalloproteases and serine proteases produced by V. parahaemolyticus and their roles in infections. Identifying the role of V. parahaemolyticus virulence-associated extracellular proteases deepens our understanding of diseases caused by this bacterium.
Topics: Animals; Bacterial Proteins; Humans; Metalloproteases; Peptide Hydrolases; Seafood; Serine Proteases; Vibrio Infections; Vibrio parahaemolyticus; Virulence; Virulence Factors
PubMed: 29752585
DOI: 10.1007/s11274-018-2453-4 -
Biochemistry Sep 2017The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is... (Review)
Review
The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is approaching oversaturation creates a challenging protein folding environment with a high probability of protein malfunction or aggregation. Failure to maintain protein homeostasis in such a setting can impair the functional integrity of the mitochondria and drive clinical manifestations. The IM is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial subcompartment. Particularly important is a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases, and the ATP-independent Oma1 protease. Herein, we will summarize the current biochemical knowledge of these proteolytic machines and discuss recent advances in our understanding of mechanistic aspects of their functioning.
Topics: Animals; Gene Expression Regulation, Enzymologic; Homeostasis; Metalloproteases; Mitochondrial Membranes; Protein Conformation
PubMed: 28806058
DOI: 10.1021/acs.biochem.7b00663 -
Microbiology Spectrum Apr 2016Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of... (Review)
Review
Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of metalloproteinases, which include the matrix metalloproteinases and the adamalysins. These enzymes have diverse substrate repertoires, and are thus involved in mediating proteolytic cascades, cell migration, and cell signaling. Dysregulation of metalloproteinases contributes to pathogenic processes, including inflammation, fibrosis, and cancer. Metalloproteinases also have important nonproteolytic functions in controlling cytoskeletal dynamics during macrophage fusion and enhancing transcription to promote antiviral immunity. This review highlights the diverse contributions of metalloproteinases to myeloid cell functions.
Topics: Animals; Humans; Metalloproteases; Myeloid Cells
PubMed: 27227311
DOI: 10.1128/microbiolspec.MCHD-0002-2015 -
Cellular and Molecular Life Sciences :... Aug 2019This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of... (Review)
Review
This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of the central nervous system. The collection covers a wide range of situations in which matrix metalloproteinases, adamalysins and meprins are regulated and in turn regulate substrates or signalling pathways involved in: nervous system development, learning and memory, neuroinflammation, degeneration and repair after traumatic and ischemic injury or neurodegenerative mechanisms underlying retinopathies, psychiatric and neurodegenerative disorders. The authors also argue that these proteinases can be considered in some cases as biomarkers or potential therapeutic targets for diseases of the nervous system. Overall, metalloproteinases are placed among the key factors that can help us better understand the cellular and molecular processes that govern neuropathophysiology and implement the strategies that result from this knowledge to open up much-needed treatment opportunities.
Topics: Central Nervous System; Humans; Matrix Metalloproteinases; Metalloproteases; Neurodegenerative Diseases; Tissue Inhibitor of Metalloproteinases
PubMed: 31175371
DOI: 10.1007/s00018-019-03172-8 -
The Journal of Clinical Investigation Jul 2022Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we...
Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knockin (KI) mouse model and found that mutant CHCHD10 aggregated in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, the survival of CHCHD10-KI mice depended on a protective stress response mediated by the mitochondrial metalloendopeptidase OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DAP3-binding cell death enhancer 1 (DELE1). We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 was critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.
Topics: Animals; Metalloproteases; Mice; Mitochondria; Mitochondrial Membranes; Mitochondrial Myopathies; Mitochondrial Proteins; Mutation; Protein Folding
PubMed: 35700042
DOI: 10.1172/JCI157504 -
Cancer Metastasis Reviews Sep 2019Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as... (Review)
Review
Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as in many diseases with cancer as the most prominent example. Nowadays, a great deal of work and literature concerns the understanding of the process of epithelial-to-mesenchymal transition (EMT) in terms of its molecular regulation and its implications for cancer. Similar statements can certainly be made regarding the investigation of the more than 500 proteases typically encoded by a mammalian genome. Specifically, the impact of proteases on tumor biology has been a long-standing topic of interest. However, although EMT actively regulates expression of many proteases and proteolytic enzymes are clearly involved in survival, division, differentiation, and movements of cells, information on the diverse roles of proteases in EMT has been rarely compiled. Here we aim to conceptually connect the scientific areas of "EMT" and "protease" research by describing how several important classes of proteolytic enzymes are regulated by EMT and how they are involved in initiation and execution of the EMT program. To do so, we briefly introduce the evolving key features of EMT and its regulation followed by discussion of protease involvement in this process.
Topics: Animals; Deubiquitinating Enzymes; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Metalloproteases; Neoplasms; Peptide Hydrolases
PubMed: 31482486
DOI: 10.1007/s10555-019-09808-2 -
Journal of Diabetes Jun 2022As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been...
BACKGROUND
As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), can be influenced by type 2 diabetes.
METHODS
A total of 1091 individuals with type 2 diabetes and 358 age-matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX-1 (sLOX-1) released by cleavage of LOX-1 by ADAM were measured by enzyme-linked immunosorbent assay kits (ELISA).
RESULTS
Serum ADAM10 was increased in subjects with diabetes compared with control (40.5 ng/mL [22.3-65.7] vs 10.3 ng/mL [7.0-17.9], respectively; P < .01); the highest levels were seen in insulin-treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX-1. Subjects with diabetes had higher serum sLOX-1 than the control (110 pg/mL [89-153] vs 104 pg/mL [85-138], respectively; P < .01), and there was a significant correlation between serum ADAM10 and sLOX-1 (r = 0.26, P < .01).
CONCLUSIONS
Serum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Disintegrins; Humans; Insulins; Metalloproteases; Scavenger Receptors, Class E
PubMed: 35705192
DOI: 10.1111/1753-0407.13287