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Advances in Pharmacology (San Diego,... 2022A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic...
A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic enzymes. ADAMs are largely membrane-bound enzymes that act as molecular scissors or sheddases of membrane-bound proteins, growth factors, cytokines, receptors and ligands, whereas ADAMTS are mainly secreted enzymes. ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and transmembrane domain. Similarly, ADAMTS family members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but instead of a transmembrane domain they have thrombospondin motifs. Most ADAMs and ADAMTS are activated by pro-protein convertases, and can be regulated by G-protein coupled receptor agonists, Ca ionophores and protein kinase C. Activated ADAMs and ADAMTS participate in numerous vascular processes including angiogenesis, vascular smooth muscle cell proliferation and migration, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs and ADAMTS also play a role in vascular malfunction and cardiovascular diseases such as hypertension, atherosclerosis, coronary artery disease, myocardial infarction, heart failure, peripheral artery disease, and vascular aneurysm. Decreased ADAMTS13 is involved in thrombotic thrombocytopenic purpura and microangiopathies. The activity of ADAMs and ADAMTS can be regulated by endogenous tissue inhibitors of metalloproteinases and other synthetic small molecule inhibitors. ADAMs and ADAMTS can be used as diagnostic biomarkers and molecular targets in cardiovascular disease, and modulators of ADAMs and ADAMTS activity may provide potential new approaches for the management of cardiovascular disorders.
Topics: ADAM Proteins; Cysteine; Disintegrins; Humans; Thrombospondins; Vascular Diseases
PubMed: 35659374
DOI: 10.1016/bs.apha.2021.11.002 -
Clinical and Experimental Hypertension... Dec 2023Thrombospondins (TSPs) play important roles in several cardiovascular diseases. However, the association between circulating (plasma) thrombospondin 2 (TSP2) and...
BACKGROUND
Thrombospondins (TSPs) play important roles in several cardiovascular diseases. However, the association between circulating (plasma) thrombospondin 2 (TSP2) and essential hypertension remains unclear. The present study was aimed to investigate the association of circulating TSP2 with blood pressure and nocturnal urine Na excretion and evaluate the predictive value of circulating TSP2 in subjects with hypertension.
METHODS AND RESULTS
603 newly diagnosed essential hypertensive subjects and 508 healthy subjects were preliminarily screened, 47 healthy subjects and 40 newly diagnosed essential hypertensive subjects without any chronic diseases were recruited. The results showed that the levels of circulating TSP2 were elevated in essential hypertensive subjects. The levels of TSP2 positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and other clinical parameters, including homeostasis model assessment of insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity, and serum triglycerides, but negatively associated with nocturnal urine Na concentration and excretion and high-density lipoprotein cholesterol. Results of multiple linear regressions showed that HOMA-IR and nocturnal Na excretion were independent factors related to circulating TSP2. Mantel-Haenszel chi-square test displayed linear relationships between TSP2 and SBP (χ = 35.737) and DBP (χ = 26.652). The area under receiver operating characteristic curve (AUROC) of hypertension prediction was 0.901.
CONCLUSION
Our study suggests for the first time that the circulating levels of TSP2 may be a novel potential biomarker for essential hypertension. The association between TSP2 and blood pressure may be, at least in part, related to the regulation of renal Na excretion, insulin resistance, and/or endothelial function.
Topics: Humans; Insulin Resistance; Ankle Brachial Index; Pulse Wave Analysis; Hypertension; Thrombospondins; Sodium; Blood Pressure; Essential Hypertension; Biomarkers
PubMed: 37943619
DOI: 10.1080/10641963.2023.2276029 -
In Vivo (Athens, Greece) 2021The pathological significance of thrombospondin (TSP)-1 and -2 in bladder cancer (BC) is well-known whereas that of TSP-3, 4 and 5 remains unclear. Our aim is to clarify...
BACKGROUND/AIM
The pathological significance of thrombospondin (TSP)-1 and -2 in bladder cancer (BC) is well-known whereas that of TSP-3, 4 and 5 remains unclear. Our aim is to clarify the pathological significance and prognostic roles of TSP-3 to 5 expression in BC patients.
PATIENTS AND METHODS
TSP-3 to 5 expression, proliferation index (PI), apoptotic index (AI) and microvessel density (MVD) were evaluated in 206 BC patients by immunohistochemical techniques.
RESULTS
TSP-5 expression was positively associated with grade, T stage, metastasis, and worse prognosis. PI in TSP-5-positive tissues was significantly higher compared to negative tissues. In contrast, AI in TSP-5-positive tissues was significantly lower compared to negative tissues. Expressions of TSP-3 and 4 were not associated with any clinicopathological features, survival, PI, or AI.
CONCLUSION
TSP-5 plays important roles in malignant behavior via cell survival regulation whereas the pathological significance of TSP-3 and TSP-4 in BC might be minimal.
Topics: Humans; Neovascularization, Pathologic; Prognosis; Thrombospondin 1; Thrombospondins; Urinary Bladder Neoplasms
PubMed: 33910854
DOI: 10.21873/invivo.12429 -
Technology and Health Care : Official... 2022Alveolar echinococcosis is an epidemic disease caused by the parasitism of Echinococcus multilocularis (Em) larvae in the intermediate or final host.
BACKGROUND
Alveolar echinococcosis is an epidemic disease caused by the parasitism of Echinococcus multilocularis (Em) larvae in the intermediate or final host.
OBJECTIVE
To identify and analyze B-cell and T-cell (Th1, Th2, and Th17) epitopes of the Em antigen protein thrombospondin 3 (TSP3).
METHODS
The amino acid sequence of TSP3 was obtained, and the secondary structural characteristics of TSP3 were predicted using bioinformatics software to further predict its potential T-cell and B-cell epitopes. The spleen lymphocytes of BALB/c mice, which were immunized with the TSP3 protein, were collected for co-culture with B-cell and T-cell antigen small peptides. The B-cell epitopes and T-cell epitope subtypes Th1, Th2, and Th17 were identified as having good immunogenicity.
RESULTS
After identification, it was found that the predominant epitopes of B cells existing in TSP3 were T18-33, T45-55, and T110-122. Furthermore, the predominant epitopes of T cells existing in TSP3 were T33-42, T45-55, T80-90, and T110-122 in the T1 subtype, T45-55, T68-77, and T92-104 in the Th2 subtype, and T53-63 and T80-90 in the Th17 subtype.
CONCLUSIONS
Six T-cell and eight B-cell dominant epitopes of the TSP3 antigen were revealed; these results may be applied in the development of a dominant epitope vaccine.
Topics: Animals; Echinococcosis; Echinococcus multilocularis; Epitopes, B-Lymphocyte; Mice; Thrombospondins
PubMed: 35068426
DOI: 10.3233/THC-212983 -
American Journal of Physiology. Cell... Nov 2021Thrombospondins (TSPs) are multidomain, secreted proteins that associate with cell surfaces and extracellular matrix. In mammals, there is a large body of data on... (Review)
Review
Thrombospondins (TSPs) are multidomain, secreted proteins that associate with cell surfaces and extracellular matrix. In mammals, there is a large body of data on functional roles of various TSP family members in cardiovascular disease (CVD), including stroke, cardiac remodeling and fibrosis, atherosclerosis, and aortic aneurysms. Coding single nucleotide polymorphisms (SNPs) of TSP1 or TSP4 are also associated with increased risk of several forms of CVD. Whereas interactions and functional effects of TSPs on a variety of cell types have been studied extensively, the molecular and cellular basis for the differential effects of the SNPs remains under investigation. Here, we provide an integrative review on TSPs, their roles in CVD and cardiovascular cell physiology, and known properties and mechanisms of TSP SNPs relevant to CVD. In considering recent expansions to knowledge of the fundamental cellular roles and mechanisms of TSPs, as well as the effects of wild-type and variant TSPs on cells of the cardiovascular system, we aim to highlight knowledge gaps and areas for future research or of translational potential.
Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelial Cells; Extracellular Matrix; Fibroblasts; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction; Thrombospondins
PubMed: 34495764
DOI: 10.1152/ajpcell.00251.2021 -
International Journal of Molecular... Sep 2021Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p...
Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.
Topics: Adult; Aged; Aged, 80 and over; Animals; Disease Models, Animal; Female; Fibrosis; Gene Expression Regulation; Humans; Male; Mice; MicroRNAs; Microscopy, Electron, Transmission; Middle Aged; Myocardium; Proteomics; Pulmonary Arterial Hypertension; Thrombospondins; Young Adult
PubMed: 34638915
DOI: 10.3390/ijms221910574 -
Nephron. Experimental Nephrology 2009Thrombospondins (TSPs) are multifunctional matricellular glycoproteins which are involved in the regulation of angiogenesis, proliferation, apoptosis, the... (Review)
Review
Thrombospondins (TSPs) are multifunctional matricellular glycoproteins which are involved in the regulation of angiogenesis, proliferation, apoptosis, the NO-cGMP-dependent protein kinase pathway and transforming growth factor (TGF) beta activation. The TSP family consists of 5 members, but currently only data on effects of TSP-1 and TSP-2 in renal disease are available. Both TSPs are hardly expressed within the healthy renal cortex and can be upregulated during renal disease. Using different animal models for renal disease, TSP-1 and -2 were found to be important regulators of pathophysiological changes during renal disease with similar and contrary effects. TSP-1 is a major activator for TGF-beta resulting in profibrotic effects in the injured kidney. In contrast, TSP-2 lacks the ability for its activation. Proapoptotic actions of TSP-1 were found during renal ischemia/reperfusion injury. While TSP-1 exerts proinflammatory actions, the currently available data for TSP-2 propose anti-inflammatory effects for this molecule. Both TSPs are known angiogenesis inhibitors, which could be proved for TSP-2, but antiangiogenic effects for TSP-1 were only evident by treatment with TSP-1 peptides in renal disease. In addition, TSP-2 can inhibit cell proliferation and matrix metalloproteinase 2 activity.
Topics: Animals; Humans; Kidney Diseases; Signal Transduction; Thrombospondins
PubMed: 19182492
DOI: 10.1159/000198235 -
International Journal of Molecular... Jun 2013Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP-1, are... (Review)
Review
Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP-1, are representative "anti"-angiogenic molecules and many studies have clarified their pathological role and clinical significance in vivo and in vitro. In fact, TSP-1 expression is associated with clinicopathological features and prognosis in many types of cancers. However, TSP-1 is a multi-functional protein and its biological activities vary according to the specific tumor environments. Consequently, there is no general agreement on its cancer-related function in urological cancers, and detailed information regarding regulative mechanisms is essential for a better understanding of its therapeutic effects and prognostic values. Various "suppressor genes" and "oncogenes" are known to be regulators and TSP-1-related factors under physiological and pathological conditions. In addition, various types of fragments derived from TSP-1 exist in a given tissue microenvironment and TSP-1 derived-peptides have specific activities. However, a detailed pathological function in human cancer tissues is not still understood. This review will focus on the pathological roles and clinical significance of TSP-1 in urological cancers, including prostate cancer, renal cell carcinoma, and urothelial cancer. In addition, special attention is paid to TSP-1-derived peptide and TSP-1-based therapy for malignancies.
Topics: Animals; Antineoplastic Agents; Humans; Peptide Fragments; Thrombospondin 1; Urologic Neoplasms
PubMed: 23749112
DOI: 10.3390/ijms140612249 -
Cold Spring Harbor Perspectives in... May 2012Thrombospondins TSP-1 and TSP-2 are potent endogenous inhibitors of angiogenesis. They inhibit angiogenesis through direct effects on endothelial cell migration,... (Review)
Review
Thrombospondins TSP-1 and TSP-2 are potent endogenous inhibitors of angiogenesis. They inhibit angiogenesis through direct effects on endothelial cell migration, proliferation, survival, and apoptosis and by antagonizing the activity of VEGF. Several of the membrane receptor systems and signal transduction molecules that mediate the effects of TSP-1 and TSP-2 have been elucidated. TSP-1 and TSP-2 exert their direct effects through CD36, CD47, and integrins. Recent data indicate that CD36 and β1 integrins collaborate to transmit the signals that are initiated by TSP-1 and TSP-2. Furthermore, these receptors appear to associate with VEGFR2 to form a platform for the integration of positive and negative signals for angiogenesis. Cross talk between pro- and antiangiogenic signal transduction pathways may enable TSP-1 and TSP-2 to inhibit angiogenesis by antagonizing survival pathways while also activating apoptotic pathways. CD36 and CD47 are both involved in the suppression of nitric oxide (NO). Advances in understanding of the molecular regulation of angiogenesis by TSP have paved the way for innovations in experimental treatment of cancers and will likely continue to offer vast avenues for discovery in other disease processes as well.
Topics: Angiogenesis Inhibitors; Antigens, CD; Antineoplastic Agents; Apoptosis; Cell Movement; Cell Proliferation; Endothelial Cells; Forecasting; Humans; Neoplasms; Neovascularization, Pathologic; Nitric Oxide; Proto-Oncogene Proteins c-fyn; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Thrombospondin 1; Thrombospondins; Vascular Endothelial Growth Factor A
PubMed: 22553494
DOI: 10.1101/cshperspect.a006627 -
Frontiers in Bioscience (Landmark... Jan 2011The human ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family of 19 secreted, multidomain proteolytic enzymes is involved in a wide range... (Review)
Review
The human ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family of 19 secreted, multidomain proteolytic enzymes is involved in a wide range of biological processes including ECM assembly and degradation, hemostasis, organogenesis and the regulation of angiogenesis. Defects in certain family members give rise to inherited human genetic diseases, while aberrant expression of other ADAMTSs has been linked to the pathogenesis of arthritis and cancer. Several ADAMTSs act as tumor or metastasis suppressors whose functions are lost either by mutation or epigenetic silencing during tumor progression. This review looks in depth at the involvement of ADAMTSs as positive and negative mediators in cancer growth and spread.
Topics: ADAM Proteins; Angiogenesis Inhibitors; Animals; Humans; Metalloproteases; Neoplasm Metastasis; Neoplasms; Thrombospondins
PubMed: 21196270
DOI: 10.2741/3827