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Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix(ECM). Matrix metalloproteinase(MMP) system can degrade most ECM components. Several lines of evidence support a role fo...
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Endothelial cell (EC) dysfunction is known to contribute to cerebral aneurysm (CA) pathogenesis. Evidence shows that damage or injury to the EC layer is the first event in CA formation. The mechanisms behind EC dysfunction in CA disease are interrelated and include hemodynamic stress, hazardous nitric oxide synthase (NOS) activity, oxidative stress...
Vascular remodelling is an integral pathological process central to a number of cardiovascular diseases. The complex interplay between distinct cell populations in the vessel wall following vascular injury leads to inflammation, cellular dysfunction, pro-growth signals in the smooth muscle cell (SMC) compartment, and the acquisition of a synthetic...
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... In addition, ZFX has also played a great role in cell migration in many studies [4,27,28]. MMPs and their inhibitor (TIMP) are involved in ECM remodeling and therefore implicated in vascular wall remodeling [29,30]. Drugs reverse the pulmonary vascular remodeling in a monocrotaline-induced PAH rat model, accompanied by inhibition of MMP-2 and MMP-9 expression [31]. ...
High expression of the zinc finger X-chromosomal protein (ZFX) correlates with proliferation, aggressiveness, and development in many types of cancers. In the current report, we investigated the efficacy of ZFX in mouse pulmonary artery smooth muscle cells (PASMCs) proliferation during pulmonary arterial hypertension (PAH). PASMCs were cultured in hypoxic conditions. Real-time PCR and western blotting were conducted to detect the expression of ZFX. Cell proliferation, apoptosis, migration, and invasion were, respectively, measured by CCK-8, flow cytometry, wound scratchy, and transwell assays. Glycolytic ability was validated by the extracellular acidification rate and oxygen consumption rate. Transcriptome sequencing technology was used to explore the genes affected by ZFX knockdown. Luciferase and chromatin immunoprecipitation assays were utilized to verify the possible binding site of ZFX and YAP1. Mice were subjected to hypoxia for 21 days to induce PAH. The right ventricular systolic pressure (RVSP) was measured and ratio of RV/LV + S was calculated. The results show that ZFX was increased in hypoxia-induced PASMCs and mice. ZFX knockdown inhibited the proliferation, migration, and invasion of PASMC. Using RNA sequencing, we identify glycolysis and YAP as a key signaling of ZFX. ZFX knockdown inhibited Glycolytic ability. ZFX strengthened the transcription activity of YAP1, thereby regulating the YAP signaling. YAP1 overexpression reversed the effect of ZFX knockdown on hypoxia-treated PASMCs. In conclusion, ZFX knockdown protected mice from hypoxia-induced PAH injury. ZFX knockdown dramatically reduced RVSP and RV/(LV + S) in hypoxia-treated mice.
... MMPs are a wide class of zinc-dependent proteases [13,14], together with their tissue blockers, are crucial for the stability of the extracellular matrix [15,16]. Essential functions are performed by these enzymes in matrix turnover, tissue remodeling, angiogenesis, and morphogenesis [17,18]. ...
Background: Pulmonary arterial hypertension (PAH) is a frequent consequence of untreated congenital heart disease (CHD). Elevated pulmonary pressure induces vascular remodeling and RV dysfunction through several mechanisms, culminating in a gradual elevation in pulmonary vascular resistance (PVR) and ultimately reversal of shunt with the progression of Eisenmenger syndrome. Objectives: To analyze the role of matrix metalloproteinase 2 (MMP-2) in pulmonary hypertension (PH) due to CHD and also to investigate if this marker has a diagnostic or prognostic value. Subjects and Methods: 25 subjects with PAH associated with CHD, 25 subjects with CHD without PH, and 25 healthy children as controls were included. Heart electrocardiography, Doppler and Two-dimensional, M-mode echocardiographic evaluation of CHD and pulmonary pressure were done. Blood specimens were collected from all subjects to assess serum MMP-2 levels by ELISA. Results: The mean MMP-2 values significantly enhanced in PAH-CHD children as compared to CHD without PAH patients and controls (P<0.05). A significant correlation was found among MMP-2 and mean pulmonary artery pressure (mPAP) and echocardiographic parameters of RV diameter and function. Sensitivity of MMP-2 as a diagnostic marker was 52% and specificity was 96%. Conclusion: Serum MMP-2 were significantly enhanced in PAH-CHD children and were correlated to severity of PH and to the echocardiographic measures of its assessment. MMP-2 could be used as an excellent diagnostic and predictive biomarker in PAH-CHD children, which could be beneficial in treatment of PH in children and prediction of their outcome.
... Matrix metallopeptidases (MMP) play an important role in angiogenesis, cell behavior, differentiation, cell proliferation, migration, and host defense (Kuzuya and Iguchi, 2003;Flamant et al., 2007). MMP-9 can disassemble the extracellular matrix (ECM) and is prominent in the vulnerable areas of atherosclerosis (Watanabe and Ikeda, 2004;Johnson, 2017). ...
In oat ingredients, flavonoids and phenolic acids are known to be the most important phenolic compounds. In phenolic compounds, wide-ranging biological responses, including antioxidative, anti-inflammatory, anti-allergic, and anti-cancer properties, were reported. Avenanthramide C (Avn C), a component of the phenolic compound of oats, has been reported to be highly antioxidant and anti-inflammatory, but its role in an anti-atherosclerosis response is unknown. The aim of this research was to assess the effect of Avn C on expression of MMP-9 on TNF-α-activated human arterial smooth-muscle cells (HASMC) and signaling involved in its anti-atherosclerosis activity. HASMC cells are known to produce inflammatory cytokines involving IL-6, IL-1β, and TNF-α during arteriosclerosis activity. Avn C specifically reduced IL-6 secretion in HASMC cells. Furthermore, we investigated whether Avn C could inhibit NF-κB nuclear protein translocation. Avn C suppressed nuclear protein translocation of NF-κB in TNF-α-stimulated HASMCs. The MMP-9 enzyme activity and expression are controlled through the MAPKs signaling path during the Avn C treatment. We confirmed that the levels of wound healing (p-value = 0.013, *p < 0.05) and migration (p-value = 0.007, **p < 0.01) are inhibited by 100 ng/ml TNF-α and 100 μM Avn C co-treated. Accordingly, Avn C inhibited the expression of MMP-9 and cell migration through the MAPK/NF-κB signaling pathway in TNF-α-activated HASMC. Therefore, Avn C can be identified and serve as disease prevention material and remedy for atherosclerosis.
... Research about the MMPs is numerous. These enzymes are involved in tissue remodeling associated with normal physiological processes, such as reproduction, embryonic development and morphogenesis (Vu and Werb, 2000;Walsh et al., 2007), postnatal development of organs (Hulboy et al., 1997;Hu et al., 2004), healing (Mohan et al., 2002), bone and cartilage remodeling (Varghese, 2006;Krane and Inada, 2008), growth of the follicle hair, angiogenesis, hippocampal synaptic physiology and plasticity (Bozdagi et al., 2007;Wang et al., 2008a); and physiopathological process such as cancer, during which they are highly expressed (Ii et al., 2006;Cai et al., 2007), cardiovascular diseases (Lijnen, 2001;Kuzuya and Iguchi, 2003), lung diseases (Greenlee et al., 2007;Coraux et al., 2008), central nervous system disorders (Rivera et al., 2004), cirrhosis and fibrosis of the liver, arthritis, atherosclerosis and skin ulcerations (Murphy and Nagase, 2008). ...
... The presence of MMPs in the blood serum is attributed to the secretion of these enzymes by components of the circulatory and immune systems, including neutrophils, monocytes, macrophages, and fibroblasts, as well as by tumor cells in response to a variety of stimuli (Woessner, 1991). MMPs play a fundamental role in the inflammatory process and are involved in the pathophysiological remodeling of the vascular wall (Kuzuya & Iguchi, 2003;Hu, Steen, Sang, & Opdenakker, 2007). ...
Highlights:
MMPs is a new approach to complement the diagnosis of caprine arthritis encephalitis. Presence of proMMP-13 may be indicative of seroconversion in acute infection.
ProMMP-9 at post-seroconversion stage can facilitate control of the disease.
MMP-2 at post-seroconversion stage indicates the presence of infection.
Abstract
Caprine arthritis encephalitis is a lentiviral disease that leads to considerable losses in goat farming. In the acute phase of viral infection, though antiviral antibodies are produced by the host's immune system, they are not sufficient to be detected by serological tests. Acute infections begin with an incubation period, during which the viral genome replicates and host innate responses are initiated. Matrix metalloproteinases (MMPs) are enzymes that play an important role in the physiological and pathological processes of tissue remodeling. The present study aimed to evaluate the expression of MMPs and their activity in the blood serum of male goats experimentally infected with caprine arthritis encephalitis virus (CAEV). Five dairy male goats, aged 3-4 years, were intravenously inoculated with CAEV Cork strain (titer: 10 5-6 TCID 50 /mL) after being tested negative for CAEV thrice at consecutive intervals of 30 days using western blot analysis and nested-PCR. The study included three stages: S1 or pre-infection stage; S2 or seroconversion stage, corresponding to the occurrence of first seroconversion; and S3 or post-seroconversion stage, corresponding to 23 weeks after seroconversion. Zymography was performed for the samples using gelatin zymography gels (12.5%), which were subjected to electrophoresis at 170V, 1A, and 300W for 50-70 min. The density of MMP-2 was found to be lower at 1 Parte da Dissertação de Mestrado do primeiro autor. Semina: Ciências Agrárias, Londrina, v. 41, n. 6, suplemento 2, p. 3165-3176, 2020 Galiza, Y. S. et al. S1 (1456.20 pixels) than that at S2 and S3 (1943.80 and 2104.40 pixels, respectively) (P < 0.05); and the density of MMP-9 was found to be lower at S3 (133.60 pixels) than that at S1 and S2 (359.60 and 370.60 pixels, respectively). The density of proMMP-2 was low at S1 and S3 (130.45 and 145.20 pixels, respectively). On the other hand, the density of proMMP-9 was statistically different between S1 and S3 (89.22 vs. 415.60 pixels). Both proMMP-2 and proMMP-9 were absent at S2. Thus, MMP-2 and MMP-9 exhibited opposite behaviors depending on the stage of infection. As the greatest activity of MMP-2 was detected at stage S3, we suggest that MMP-2 can be used as a biomarker for complementary diagnosis of acute CAEV infection. In addition, the presence of proMMP-13 can be used to indicate active viral infection. Resumo A encefalite por artrite caprina é uma doença lentiviral que leva a perdas consideráveis na criação de caprinos. Na fase aguda da infecção viral, embora os anticorpos antivirais sejam produzidos pelo sistema imunológico do hospedeiro, eles não são suficientes para serem detectados por testes sorológicos. As infecções agudas começam com um período de incubação, durante o qual o genoma viral se replica e as respostas inatas do hospedeiro são iniciadas. As metaloproteinases da matriz (MMPs) são enzimas que desempenham um papel importante nos processos fisiológicos e patológicos da remodelação tecidual. O presente estudo teve como objetivo avaliar a expressão de MMPs e sua atividade no soro sanguíneo de reprodutores caprinos infectados experimentalmente pelo vírus da encefalite por artrite caprina (CAEV). Cinco machos caprinos, com idades entre 3-4 anos, foram inoculadas por via intravenosa com a cepa de CAEV Cork (título: 10 5-6 TCID 50 /mL) após serem testados negativamente para CAEV três vezes em intervalos consecutivos de 30 dias usando a análise de western blot e nested-PCR. O estudo incluiu três etapas: estágio S1 ou pré-infecção; S2 ou estágio de soroconversão, correspondente à ocorrência de primeira soroconversão; e S3 ou pós-soroconversão, correspondendo a 23 semanas após a soroconversão. A zimografia foi realizada para as amostras utilizando gel de gelatina (12,5%), que foram submetidos à eletroforese em 170V, 1A e 300W por 50-70 min. Verificou-se que a densidade de MMP-2 era menor em S1 (1456,20 pixels) do que em S2 e S3 (1943,80 e 2104,40 pixels, respectivamente) (P < 0,05); e a densidade de MMP-9 foi menor em S3 (133,60 pixels) do que em S1 e S2 (359,60 e 370,60 pixels, respectivamente). A densidade do proMMP-2 era baixa em S1 e S3 (130,45 e 145,20 pixels, respectivamente). Por outro lado, a densidade do proMMP-9 foi estatisticamente diferente entre S1 e S3 (89,22 vs. 415,60 pixels). ProMMP-2 e proMMP-9 estavam ausentes no S2. Assim, MMP-2 e MMP-9 exibiram comportamentos opostos, dependendo do estágio da infecção. Como a maior atividade da MMP-2 foi detectada no estágio S3, sugerimos que a MMP-2 possa ser usada como biomarcador para o diagnóstico complementar de infecção aguda por CAEV. Além disso, a presença de proMMP-13 pode ser usada para indicar infecção viral ativa.
... The precise mechanism of aortic mechanism is still unknown. MMP-9 degrades extracellular matrix elastin and collagen (Freestone et al., 1995;Kuzuya and Iguchi, 2003). MMP-2 MMP-3, andMMP-9 which possess elastolytic and collagenolytic activities, are involved in the development of aortic aneurysm (Ailawadi et al., 2003;Kotze and Ahmad, 2011;Rabkin, 2017). ...
Aortic aneurysms are mostly asymptomatic but have high rates of mortality when there is rupture or dissection. Matrix metalloproteinases is involved in the evolution of aortic aneurysms. Advanced glycation end products and its cell receptor RAGE (receptor for AGE) and sRAGE (soluble receptor of AGE) have been suggested to be involved in the pathogenesis of numerous diseases. This review addresses the role of AGE, RAGE and AGE-RAGE stress (AGE/sRAGE) in the pathogenesis of abdominal aortic aneurysm and thoracic aortic aneurysm in humans. AGERAGE interaction not only increases the generation of reactive oxygen species and inflammatory cytokines, but also activates NF-kB. There are increases in the levels of AGE in aortic tissue, skin and serum in patients with thoracic aortic aneurysm and abdominal aortic aneurysm. Levels of RAGE in tissue are elevated in abdominal aortic aneurysm. AGE-RAGE stress is elevated in patients with thoracic aortic aneurysm. The serum levels of cytokines and Matrix metalloproteinases are elevated in patients with thoracic aortic aneurysm and abdominal aortic aneurysm. The levels of AGE and AGE-RAGE stress correlate positively with cytokines and Matrix metalloproteinases, but the serum levels of sRAGE correlate negatively with cytokines and Matrix metalloproteinases. Cytokines levels are positively correlated with the levels of Matrix metalloproteinases in patients with thoracic aortic aneurysm. In conclusion, elevated levels of AGE, RAGE and AGE-RAGE stress, and reduced levels of sRAGE increase the levels of cytokines that in turn increase the production of Matrix metalloproteinases resulting in formation of aortic aneurysms. The data suggest that AGE-RAGE stress is involved in the pathogenesis of aortic aneurysms. Treatment options have also been discussed.
... Matrix metalloproteinases (MMP), endopeptidases belonging to the matrixin family, can degrade almost all extracellular matrix (EMC) components. Dysregulation of the synthesis and breakdown of EMC is responsible for both vascular remodeling and development of atherothrombotic syndromes [147]. However, Mannello reported that the measurement of MMP in serum and plasma is not interchangeable [148]. ...
The constrained economic context leads laboratories to centralize their routine analyses on high-throughput platforms, to which blood collection tubes are sent from peripheral sampling sites that are sometimes distantly located. Providing biochemistry results as quickly as possible implies to consolidate the maximum number of tests on a minimum number of blood collection tubes, mainly serum tubes and/or tubes with anticoagulants. However, depending on the parameters and their pre-analytical conditions, the type of matrix – serum or plasma – may have a significant impact on results, which is often unknown or underestimated in clinical practice. Importantly, the matrix-related effects may be a limit to the consolidation of analyses on a single tube, and thus must be known by laboratory professionals.
The purpose of the present critical review is to put forward the main differences between using serum and plasma samples on clinical biochemistry analyses, in order to sensitize laboratory managers to the need for standardization. To enrich the debate, we also provide an additional comparison of serum and plasma concentrations for approximately 30 biochemistry parameters.
Properties, advantages, and disadvantages of serum and plasma are discussed from a pre-analytical standpoint – before, during, and after centrifugation – with an emphasis on the importance of temperature, delay, and transport conditions. Then, differences in results between these matrices are addressed for many classes of biochemistry markers, particularly proteins, enzymes, electrolytes, lipids, circulating nucleic acids, metabolomics markers, and therapeutic drugs. Finally, important key-points are proposed to help others choose the best sample matrix and guarantee quality of clinical biochemistry assays. Moreover, awareness of the implications of using serum and plasma samples on various parameters assayed in the laboratory is an important requirement to ensure reliable results and improve patient care.
... MMP-2 expression is associated with the induction of SMC hyperplasia during atherosclerosis and restenosis. Furthermore, MMP-2 plays a role in the migration of SMCs, which contributes to the intimal thickening of vascular lesions in vivo 30,39 . Our results revealed that pretreatment with CBA inhibited the PDGF-induced increase in MMP-2 expression and its proteolytic activity in a dose-dependent manner. ...
Excessive migration of vascular smooth muscle cells (VSMCs) after vascular injury contributes to the development of occlusive vascular disease. Inhibition of VSMC migration is a validated therapeutic modality for occlusive vascular diseases, such as atherosclerosis and restenosis. We investigated the inhibitory effect of chebulinic acid (CBA) on cell migration and matrix metalloproteinase (MMP)-2 activation in platelet-derived growth factor (PDGF)-BB-induced mouse and human VSMCs. CBA significantly inhibited PDGF-BB-induced migration in mouse and human VSMCs, without inducing cell death. Additionally, CBA significantly blocked PDGF-BB-induced phosphorylation of the PDGF receptor (PDGF-R), Akt, and extracellular signal-regulated kinase (ERK)1/2 by inhibiting the activation of the PDGF-BB signalling pathway. In both mouse and human VSMCs, CBA inhibited PDGF-induced MMP-2 mRNA and protein expression as well as the proteolytic activity of MMP-2. Moreover, CBA suppressed sprout outgrowth formation of VSMCs from endothelium-removed aortic rings as well as neointima formation following rat carotid balloon injury. Taken together, our findings indicated that CBA inhibits VSMC migration by decreasing MMP-2 expression through PDGF-R and the ERK1/2 and Akt pathways. Our data may improve the understanding of the antiatherogenic effects of CBA in VSMCs.
... During the migration of smooth muscle cells (SMCs) and the plaque rupture in atherosclerosis, matrix metalloproteinases (MMPs) have been recognized to catalyze the degradation of fibrous cap components such as collagens, elastin, fibronectin and proteoglycans (7)(8)(9), and thus contribute to the vulnerability of atherosclerotic plaques. Among the more than 20 types of MMPs (10), MMP-1, -2, -3, -7, -8, -9, -13, and -14 have been reported to be increased at atherosclerotic lesions in human and animal models (9,(11)(12)(13)(14). MMP-1 and MMP-14 predominantly localize in SMCs (15,16) and macrophages (13), whereas MMP-8 and -13 are produced from neutrophils (14) and macrophages (13), respectively. ...
Oxidized low-density lipoprotein (oxLDL) has been reported to contribute to the development and progression of atherosclerosis, which is also stimulated by viral infections, such as influenza. However, the mechanism underlining the promotion of atherosclerosis by both risk factors remains unclear. In the present study, we investigated the expression of matrix metalloproteinase-9 (MMP-9), which is one of key mediators of atherosclerosis progression, in oxLDL-treated human umbilical vein endothelial cells (HUVEC)-C cells. The infection efficiency of H1N1 pdm2009 influenza virus in the HUVEC-C cells was subsequently examined, and the expression of MMP-9 and proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, were determined in the virus-infected HUVEC-C cells, with or without oxLDL treatment. Results demonstrated that oxLDL treatment with 10, 20 or 50 µg/ml markedly upregulated MMP-9 expression at the mRNA and protein levels. H1N1 pdm2009 influenza virus efficiently infected the HUVEC-C cells and significantly promoted the expression of MMP-9, TNF-α, IL-1β and IL-6, synergistically with the oxLDL treatment. Taken together, these results demonstrated for the first time that oxidized-LDL treatment and influenza virus infection synergistically enhance the expression of MMP-9 and proinflammatory cytokines in human endothelial cells, suggesting that both factors are potent stimulators in atherosclerotic impairment to endothelial cells.
... Berbagai zat gizi mikro sangat dibutuhkan untuk menunjang peristiwa imunologik (Aydemir et al., 2009;Elenkov et al., 2001;Kuzuya & Iguchi, 2003;Rundaugh, 2005;Hewison, 2011) dan hormonal dalam proses implantasi dan plasentasi pada awal kehamilan (Stephanou, 1994;Stephanou & Handwerger, 1995;Evan et al., 2006). Jika keberhasilan kehamilan ditentukan oleh keberhasilan implantasi dan plasentasi, maka suplementasi MMN semestinya diberikan pada masa sebelum hamil agar dapat menunjang masa kritis awal kehamilan. ...
... Zn berperan dalam proses implantasi dan plasentasi karena merupakan bagian dari enzim Matrix Metallo Proteinase (MMP) yang berperan dalam proses remodeling pembuluh darah arteri (Kuzuya & Iguchi, 2003;Rundhaug, 2005). Selain itu Zn merangsang ekspresi IFNɣ (Aydemir et al., 2009), selanjutnya IFNɣ yang disekresi oleh sel uNK berperan untuk menginisiasi modifikasi pembuluh darah uteri serta membentuk integritas jaringan desidua (Ashkar et al., 2000). ...
The role of multi-micronutrients (MMN) supplementation to improve birth weight is still debatable. Its role on pregnancy outcomes may involve the Interleukin 12 (IL-12) and human Placental Lactogen (hPL). This research was conducted to evaluate the effect of multi-micronutrients supplementation during preconception period on birth weight and fetal viability in relation to IL-12 and hPL concentration during the 3rd trimester of pregnancy. A randomized double blind community-based trial was conducted at District of Probolinggo East Java. A two-arms study consists of group I that received placebo during preconception period and continued with daily iron and folic acid (IFA) during pregnancy, and group II that received multi-micronutrient containing 15 micronutrients, 2 other days during preconception, and continued with daily dose during pregnancy. A sample size of 115 pregnancy outcomes was obtained from 420 brides-to-be. The primary outcome variables are birth weight and fetal viability. The intervening variables are concentration of IL-12 and hPL in the last trimester, gestational age, maternal weight gain and placental weight. Maternal iron status and serum retinol were also assessed. Data were analyzed using MANCOVA and ANCOVA to evaluate effect of supplementation. Causal relationships were tested by using Structural Equation Modeling (SEM). The characteristic between treatment group and control group were not different (Box’s M value p = 0,398; Hotelling's Trace value p = 0,478I). Results show that compare to iron folic acid supplementation, subjects who received multi-micronutrients supplementation beginning at preconception period, have lower IL-12 concentration by 0.10 pg/mL (p=0,665), higher hPL concentration by 1.14 mg/L (p=0,014), longer gestational age by 1.66 weeks (p=0,539), no difference of total weight gain (p=0,995), and significantly higher of placental weight and birth weight by 83.59 grams (p=0,000) and 309.89 grams (p=0,000) respectively. Effect of Iron folic acid and MMN supplementation on fetal viability is not different (p=0,364), but multi-micronutrient supplement tends to improve intra-uterine fetal survival. It implies that multi-micronutrient supplementation beginning at 2-6 months prior to pregnancy and being continued during pregnancy improves birth weight by increasing hPL production and placental weight, as well as controlling maternal immune response, particularly reducing IL-12 concentration in last trimester. Fetal viability is directly influence by gestational age. In addition, MMN influence fetal viability by increasing gestational age.
