RESUMEN
Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.
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Envejecimiento/metabolismo , Proteínas Sanguíneas/farmacología , Sangre Fetal/química , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Plasticidad Neuronal/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Animales , Proteínas Sanguíneas/administración & dosificación , Proteínas Sanguíneas/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Femenino , Hipocampo/citología , Humanos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Plasticidad Neuronal/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Análisis por Matrices de Proteínas , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Inhibidor Tisular de Metaloproteinasa-2/administración & dosificación , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/farmacologíaRESUMEN
OBJECTIVES: Inhalation of immunostimulatory bacterial DNA segments (cytosine-phosphate-guanosine-oligodeoxynucleotides, CpG-ODN) normalizes clinical and cytologic parameters in severe equine asthma. We hypothesized that CpG-ODN inhalation also reduces the misbalance of elastinolytic activity in asthmatic horses. METHODS: Twenty asthmatic horses diagnosed by clinical examinations using a scoring system were included. All horses inhaled CpG-ODNs for 14 days in 2-day intervals. Matrix metalloproteinase (MMP-2/-9) and tissue inhibitors of metalloproteinase (TIMP-1/-2) concentrations were measured in tracheal aspirates using equine sandwich ELISAs before and 2 and 6 weeks after CpG-ODN inhalation. RESULTS: MMP and TIMP concentrations correlated with the results of clinical scoring in all stages of equine asthma. Inhalation therapy led to significant reductions in clinical scores. MMP-2, MMP-9, and TIMP-2 concentrations were significantly reduced immediately, and all MMP and TIMP concentrations 6 weeks after therapy. DISCUSSION: In equine asthma, overexpression of MMPs contributes to pathological tissue destruction, while TIMPs counteract MMPs with overexpression leading to fibrosis formation. The results of this study show that CpG-ODN inhalation may be an effective therapy to address a misbalance in equine asthma. CONCLUSIONS: Misbalance of elastinolytic activity seems to improve by CpG-ODN inhalation for at least 6 weeks posttherapy, which may reduce the remodeling of the extracellular matrix. Further studies should evaluate this effect in comparison to glucocorticoid inhalation therapy. SIGNIFICANCE: CpG-ODN inhalation may be an effective therapy in the prevention of pulmonary fibrosis formation in equine asthma.
Asunto(s)
Administración por Inhalación , Asma/veterinaria , Enfermedades de los Caballos/terapia , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Metaloproteasas/metabolismo , Oligodesoxirribonucleótidos/administración & dosificación , Animales , Asma/inmunología , Asma/terapia , Matriz Extracelular/metabolismo , Enfermedades de los Caballos/inmunología , Caballos , Inmunización , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
BACKGROUND/AIMS: LncRNA GAS5, a growth suppressor, has been reported to exert anti-tumor actions in various cancers, whereas the exact mechanism underling the anti-tumor action is still unclear. This study was aimed to investigate the effect of lncRNA GAS5 on osteosarcoma and tried to decode the underling mechanisms. METHODS: Expressions of lncRNA GAS5 in MG-63 cells were silenced by shRNA transfection, while were overexpressed by vector transfection. Cell viability, migration, invasion and apoptosis were respectively assessed by MTT, Transwell assay and flow cytometry. Regulations between lncRNA GAS5 and miR-203a, as well as between miR-203a and TIMP2 were detected by qPCR, western blot and dual luciferase activity assay. RESULTS: LncRNA GAS5 was down-regulated in MG-63 and OS-732 cells compared to hFOB1.19 cells. Silence of lncRNA GAS5 significantly promoted MG-63 cells viability, migration and invasion, and up-regulated Cyclin D1, Cyclin B1, CDK1 and CDK4 expressions. miR-203a was negatively regulated by lncRNA GAS5. The promoting activities of lncRNA GAS5 silence on MG-63 cells growth and metastasis were reversed by miR-203a suppression. TIMP2 was a target of miR-203a and the anti-growth and anti-metastasis actions of miR-203a suppression were reversed by TIMP2 silence. Further, lncRNA GAS5 silence, miR-203a overexpression, and TIMP2 silence could activate PI3K/AKT/GSK3ß signaling while block NF-κB signaling. CONCLUSION: LncRNA GAS5 might be a tumor suppressor in osteosarcoma via sponging miR-203a, sequestering miR-203a away from TIMP2.
Asunto(s)
MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Antagomirs/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , FN-kappa B/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/genética , Transducción de Señal , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Regulación hacia ArribaRESUMEN
Hepatocellular carcinoma (HCC) is a malignant cancer worldwide; lacking biomarkers for early prognostication contributes to its high lethality. Herein, we report a novel biomarker, exosome delivered miR-93, is up-regulated in HCC cell line media and serum samples of HCC patients. We measured the proliferation and invasion ability of HCC cell lines following exosomal miR-93 treatment. After prediction with online algorithms, we further confirmed that TP53INP1, TIMP2 and CDKN1A are direct targets of miR-93 by dual-luciferase reporter assay. In addition, the diagnostic value of exosomal miR-93 was evaluated by qPCR and ROC analysis. The significant correlation between serum exosomal miR-93 and clinical information including stage, tumor size were observed. Furthermore, the survival differences of HCC patients with high or low miR-93 were statistically significant using Kaplan-Meier analysis. In summary, our work identified exosomal miR-93 as a novel biomarker for both diagnosis and prognosis in HCC.
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Carcinoma Hepatocelular/genética , Proteínas Portadoras/antagonistas & inhibidores , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Proteínas de Choque Térmico/antagonistas & inhibidores , Neoplasias Hepáticas/genética , MicroARNs/genética , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Exosomas/genética , Exosomas/metabolismo , Femenino , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica/genética , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of fibrous extracellular matrix. Transforming growth factor-beta (TGF-ß) is a central profibrotic mediator, and targeting TGF-ß is a promising strategy in the development of drugs for the treatment of fibrosis. Therefore, the effect of LY2109761, a small molecule inhibitor against TGF-ß with targets beyond TGF-ß signaling, on fibrogenesis was elucidated in vitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices). Our results displayed an anti-fibrotic effect of LY2109761, as it markedly down-regulated gene and protein expression of collagen type 1, as well as gene expression of the inhibitor of metalloproteinases 1. This effect on fibrosis markers was partially mediated by targeting TGF-ß signaling, seeing that LY2109761 inhibited TGF-ß1 gene expression and SMAD2 protein phosphorylation. Interestingly, particularly at a high concentration, LY2109761 decreased SMAD1 protein phosphorylation and gene expression of the inhibitor of DNA binding 1, which appeared to be TGF-ß-independent effects. In conclusion, LY2109761 exhibited preclinical anti-fibrotic effects via both TGF-ß-dependent and -independent pathways. These results illustrate that small molecule inhibitors directed against TGF-ß could possibly influence numerous signaling pathways and thereby mitigate fibrogenesis.
Asunto(s)
Fibrosis/tratamiento farmacológico , Pirazoles/farmacología , Pirroles/farmacología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Colágeno Tipo I/antagonistas & inhibidores , Colágeno Tipo I/biosíntesis , Regulación hacia Abajo , Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Fosforilación , Ratas , Ratas Wistar , Proteína Smad1/antagonistas & inhibidores , Proteína Smad2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidoresRESUMEN
We recently demonstrated that luteal cells flow out from the ovary via lymphatic vessels during luteolysis. However, the regulatory mechanisms of the outflow of luteal cells are not known. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basal membrane, and tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs. To test the hypothesis that MMP expression in luteal cells is regulated by luteolytic factors, we investigated the effects of prostaglandin F2α (PGF), interferon γ (IFNG) and tumor necrosis factor α (TNF) on the mRNA expression of MMPs and TIMPs in cultured luteal cells. Luteal cells obtained from the CL at the mid-luteal stage (days 8-12 after ovulation) were cultured with PGF (0.01, 0.1, 1 µM), IFNG (0.05, 0.5, 5 nM) and TNF (0.05, 0.5, 0.5 nM) alone or in combination for 24 h. PGF and IFNG significantly increased the expression of MMP-1 mRNA. In addition, 1 µM PGF in combination with 5 nM IFNG stimulated MMP-1 and MMP-9 mRNA expression significantly more than either treatment alone. In contrast, IFNG significantly decreased the level of MMP-14 mRNA. The mRNA expression of TIMP-1, which preferentially inhibits MMP-1, was suppressed by 5 nM INFG. One µM PGF and 5 nM IFNG suppressed TIMP-2 mRNA expression. These results suggest a new role of MMPs: luteal MMPs stimulated by PGF and IFNG break down the extracellular matrix surrounding luteal cells, which accelerates detachment from the CL during luteolysis, providing an essential prerequisite for outflow of luteal cells from the CL to lymphatic vessels.
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Dinoprost/metabolismo , Regulación Enzimológica de la Expresión Génica , Interferón gamma/metabolismo , Células Lúteas/enzimología , Luteólisis/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Mataderos , Animales , Animales Endogámicos , Apoptosis , Bovinos , Células Cultivadas , Regulación hacia Abajo , Femenino , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Japón , Células Lúteas/citología , Células Lúteas/metabolismo , Fase Luteínica/metabolismo , Metaloproteinasa 1 de la Matriz/química , Metaloproteinasa 1 de la Matriz/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Inhibidor Tisular de Metaloproteinasa-1/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
The transition from liver fibrosis to hepatocellular carcinoma (HCC) has been suggested to be a continuous and developmental pathological process. MicroRNAs (miRNAs) are recently discovered molecules that regulate the expression of genes involved in liver disease. Many reports demonstrate that miR-483-5p and miR-483-3p, which originate from miR-483, are up-regulated in HCC, and their oncogenic targets have been identified. However, recent studies have suggested that miR-483-5p/3p is partially down-regulated in HCC samples and is down-regulated in rat liver fibrosis. Therefore, the aberrant expression and function of miR-483 in liver fibrosis remains elusive. In this study, we demonstrate that overexpression of miR-483 in vivo inhibits mouse liver fibrosis induced by CCl4 . We demonstrate that miR-483-5p/3p acts together to target two pro-fibrosis factors, platelet-derived growth factor-ß and tissue inhibitor of metalloproteinase 2, which suppress the activation of hepatic stellate cells (HSC) LX-2. Our work identifies the pathway that regulates liver fibrosis by inhibiting the activation of HSCs.
Asunto(s)
Carcinoma Hepatocelular/prevención & control , Células Estrelladas Hepáticas/citología , Cirrosis Hepática/prevención & control , MicroARNs/genética , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/farmacología , Animales , Tetracloruro de Carbono/toxicidad , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevención & control , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/metabolismo , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , ARN Mensajero/genética , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
BACKGROUND: Angiogenesis is usually driven by inflammation. Matrix metalloproteinases MMP-3 and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 are implicated in vascular remodeling. TIMP-2 exhibits antiangiogenic properties. Statins show benefits that are additional to lipid lowering including pro- and antiangiogenic properties. Atherosclerotic lesions in the coronary arteries have been well studied, but less is known about the fine terminal branches of the myocardial vasculature. METHODS: To examine this, we studied rosuvastatin (RSV) treatment in ApoE knockout (ApoE(-/-)) mice fed a high cholesterol (HC) diet. Hearts from ApoE(-/-) mice on a normal diet, HC diet and HC diet with RSV were harvested to determine MMP-3, MMP-9, TIMP-1, TIMP-2, vascular endothelial growth factor (VEGF)-A and estrogen receptor-α (ER-α) mRNA. RESULTS: RSV inhibited TIMP-1 and TIMP-2 expression and enhanced myocardial VEGF-A and ER-α expression, independently of plasma lipid level changes, but had no effect on MMP-3 and MMP-9 expression. CONCLUSIONS: These modulations of TIMPs, VEGF and ER-α expression induced by RSV may act as local stimulating factors for arteriolar growth in the myocardium.
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Apolipoproteínas E/genética , Fluorobencenos/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Pirimidinas/farmacología , Sulfonamidas/farmacología , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Animales , Colesterol en la Dieta/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lípidos/sangre , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Rosuvastatina Cálcica , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hypoxia, which characterizes ischemia, trauma, inflammation, and solid tumors, recruits monocytes, immobilizes them, and alters their function, leading to an anti-inflammatory and proangiogenic phenotype. Monocyte extravasation from the circulation and their migration in tissues are partially mediated by the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The mechanisms evoked by hypoxia that regulate monocyte migration and activation are not entirely clear. Specifically, the effect of hypoxia on TIMPs in these cells has hardly been investigated. We show that hypoxia reduces TIMP-2 secretion from human primary monocytes and from the monocyte-like cell lines U937 and THP-1 by three- to fourfold (P < 0.01), by inhibiting TIMP-2 transcription through mechanisms that involve the transcription factor SP-1. Hypoxia also lowers TIMP-2 protein secretion from human endothelial cells (by 2-fold, P < 0.05). TIMP-2 levels do not influence the reduced migration of THP-1 cells in hypoxia; however, low TIMP-2 levels enhance endothelial cell migration/proliferation, their ability to form tubelike structures in vitro, and the appearance of mature blood vessels in a Matrigel plug assay in vivo. Thus we conclude that reduced TIMP-2 levels secreted from both hypoxic monocytes and endothelial cells are proangiogenic.
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Regulación hacia Abajo , Hipoxia/metabolismo , Monocitos/metabolismo , Neovascularización Fisiológica , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Regulación hacia Arriba , Animales , Secuencia de Bases , Línea Celular , Inhibición de Migración Celular/genética , Movimiento Celular/genética , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Hipoxia/patología , Hipoxia/fisiopatología , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Monocitos/patología , Neovascularización Fisiológica/genética , Neovascularización Fisiológica/fisiología , Factor de Transcripción Sp1/fisiología , Inhibidor Tisular de Metaloproteinasa-2/biosíntesis , Inhibidor Tisular de Metaloproteinasa-2/genética , Células U937 , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium. We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis. METHODS: We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers. RESULTS: We observed that TGF-α was mainly shed by ADAM17 in PBECs from all groups. Interestingly, IL-8 production occurred independently from ADAM17 and TGF-α shedding, but was significantly inhibited by broad-spectrum metalloproteinase inhibitor TAPI-2. CSE did not induce ADAM17-dependent TGF-α shedding, while it slightly augmented the production of IL-8. This was accompanied by reduced endogenous inhibitor of metalloproteinase (TIMP)-3 levels, suggesting that CSE does not directly but rather indirectly alter activity of ADAM17 through the regulation of its endogenous inhibitor. Furthermore, whereas baseline TGF-α shedding was lower in COPD PBECs, the early release of IL-8 (likely due to its shedding) was higher in PBECs from COPD than healthy smokers. Importantly, this was accompanied by lower TIMP-2 levels in COPD PBECs, while baseline TIMP-3 levels were similar between groups. CONCLUSIONS: Our data indicate that IL-8 secretion is regulated independently from ADAM17 activity and TGF-α shedding and that particularly its early release is differentially regulated in PBECs from COPD and healthy smokers. Since TIMP-2-sensitive metalloproteinases could potentially contribute to IL-8 release, these may be interesting targets to further investigate novel therapeutic strategies in COPD.
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Mediadores de Inflamación/metabolismo , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/enzimología , Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Proteína ADAM17 , Adulto , Anciano , Células Cultivadas , Femenino , Humanos , Mediadores de Inflamación/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Humo/efectos adversos , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , NicotianaRESUMEN
The endothelial cell (EC)-derived tissue inhibitor of metalloproteinase-2 (TIMP-2) and pericyte-derived TIMP-3 are shown to coregulate human capillary tube stabilization following EC-pericyte interactions through a combined ability to block EC tube morphogenesis and regression in three-dimensional collagen matrices. EC-pericyte interactions strongly induce TIMP-3 expression by pericytes, whereas ECs produce TIMP-2 in EC-pericyte cocultures. Using small interfering RNA technology, the suppression of EC TIMP-2 and pericyte TIMP-3 expression leads to capillary tube regression in these cocultures in a matrix metalloproteinase-1 (MMP-1)-, MMP-10-, and ADAM-15 (a disintegrin and metalloproteinase-15)-dependent manner. Furthermore, we show that EC tube morphogenesis (lumen formation and invasion) is primarily controlled by the TIMP-2 and -3 target membrane type (MT) 1 MMP. Additional targets of these inhibitors include MT2-MMP and ADAM-15, which also regulate EC invasion. Mutagenesis experiments reveal that TIMP-3 requires its proteinase inhibitory function to induce tube stabilization. Overall, these data reveal a novel role for both TIMP-2 and -3 in the pericyte-induced stabilization of newly formed vascular networks that are predisposed to undergo regression and reveal specific molecular targets of the inhibitors regulating these events.
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Inhibidores de la Angiogénesis/fisiología , Capilares/crecimiento & desarrollo , Endotelio Vascular/crecimiento & desarrollo , Pericitos/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/fisiología , Inhibidor Tisular de Metaloproteinasa-3/fisiología , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Inhibidores de la Angiogénesis/genética , Animales , Capilares/citología , Capilares/metabolismo , Bovinos , Colágeno , Embrión de Mamíferos/irrigación sanguínea , Embrión de Mamíferos/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Regulación de la Expresión Génica , Humanos , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 10 de la Matriz/metabolismo , Metaloproteinasas de la Matriz Asociadas a la Membrana/genética , Metaloproteinasas de la Matriz Asociadas a la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Modelos Cardiovasculares , Mutagénesis , Interferencia de ARN , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-3/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-3/genéticaRESUMEN
BACKGROUND: Rheumatoid Arthritis (RA) is a complex disease involving an unknown number of genes, and affecting a large number of organs, tissues, and sites across the body. It is affecting approximately 1% of the population worldwide. The safety and therapeutic efficacy of ß-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property has been demonstrated under in vitro, in vivo examinations and clinical trials phase 1/11 in Ankylosing Spondylitis (AS) patients in addition to phase I/11 and 111 in Rheumatoid Arthritis (RA) patients. OBJECTIVE: In this study, our goal is to evaluate the therapeutic efficacy of oral administration of M2000 on gene expression of the matrix metalloproteinase (MMP2, MMP9) and tissue inhibitor of metalloproteinase (TIMP1, TIMP2) as inflammatory molecules in the progression of rheumatoid arthritis. METHODS: The study has included 15 RA patients who had an insufficient response to the conventional drug. Therefore, mannuronic acid was used as an additive to the conventional regime. The research was a single-blinded study. The dose of M2000 was 500mg orally twice per day for 12 weeks. There were 15 healthy participants considered as control. Blood samples have been collected from both groups once from the healthy control and twice from RA patients before and after treatment with M2000. The Peripheral Blood Mononuclear Cells (PBMCs) were isolated for assessment of the gene expression level of MMP2, MMP9, TIMP1, and TIMP2 using the real-time PCR method. RESULTS: The gene expression level of MMP2 and MMP9 reported a significant reduction in RA patients after treatment with M2000 compared to before treatment. On the other hand, the gene expression level of TIMP2 demonstrated a significant increase in RA patients after treatment with mannuronic acid compared to before treatment, but there was no significant difference between the group of RA patients before treatment and the control group. Vice versa to other molecules, there was no significant difference in the level of TIMP1 in compression with RA patients before and after treatment. CONCLUSION: our findings proved that the ß -D- mannuronic acid) as a novel NSAID with immunosuppressive property has a significant effect on the gene expression level of MMP2, MMP9 and TIMP2 molecules in RA patients.
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Antiinflamatorios no Esteroideos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Ácidos Hexurónicos/farmacología , Inmunosupresores/farmacología , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Administración Oral , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Reumatoide/inmunología , Quimioterapia Combinada/métodos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Voluntarios Sanos , Ácidos Hexurónicos/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Pancreatic stellate cells (PSCs) play a key role in fibrogenesis associated with acute and chronic pancreatitis. Pancreatitis-associated protein (PAP), an acute-phase protein, is dramatically upregulated during acute and chronic pancreatitis. Assuming a protective role of PAP, we investigated its effects on human PSCs. METHODS: PSCs were obtained by outgrowth from fibrotic human pancreas tissue. PAP was expressed in the yeast Pichia pastoris. PAP was added at 10 ng/ml to cultured PSCs. Cell proliferation was determined by bromodeoxyuridine incorporation. PSC migration was assessed by a wound healing assay. Collagen types I and III, fibronectin, matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) were demonstrated on protein and mRNA level. RESULTS: PAP had no significant effect on PSC proliferation and migration. Cell-associated fibrillar collagen types I and III and fibronectin increased after addition of PAP to PSCs. PAP diminished the expression of MMP-1 and -2 and TIMP-1 and -2 and their concentrations in PSC supernatants. RECK was detected on the surface of PSCs and its expression was reduced after PAP application. CONCLUSIONS: Our data offer new insights into the biological functions of PAP, which may play an important role in wound healing response and cell-matrix interactions.
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Antígenos de Neoplasias/fisiología , Biomarcadores de Tumor/fisiología , Lectinas Tipo C/fisiología , Inhibidores de la Metaloproteinasa de la Matriz , Glicoproteínas de Membrana/biosíntesis , Páncreas/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-1/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Proteínas Ligadas a GPI , Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Páncreas/citología , Proteínas Asociadas a Pancreatitis , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: In this study, we investigated the effect of basic fibroblast growth factor (bFGF) and dexamethasone (Dex) on mRNA expressions of collagen (COL) type I, III and X, matrix metalloproteinases (MMP)-1, -2, -3 and -9 and tissue inhibitors of metalloproteinases (TIMP)-1 and -2, and also on mineralization and morphology of periodontal ligament (PDL) cells. MATERIAL AND METHODS: Periodontal ligament cells were obtained from premolar teeth extracted for orthodontic reasons. Periodontal ligament cells were cultured with Dulbecco's modified Eagle's medium containing: (1) 5% fetal bovine serum (FBS); (2) 5% FBS + ascorbic acid (AA, 50 microg/mL); (3) 5% FBS + Dex (10(-7) m) + AA; (4) 5% FBS + bFGF (10 ng/mL) + AA; or (5) 5% FBS + Dex (10(-7) m) + bFGF + AA. Cells within each group were evaluated for gene expression profile using semi-quantitative reverse transcriptase-polymerase chain reaction for COL I, III and X, MMP-1, -2, -3 and -9 and TIMP-1 and -2 on days 14 and 21 and for biomineralization by von Kossa stain in vitro on day 21. Images of PDL cells were examined using a phase contrast microscope. RESULTS: Basic fibroblast growth factor stimulated MMP-1, MMP-3 and MMP-9 mRNA expressions and inhibited TIMP-2 mRNA expression. Treatment of cells with Dex + bFGF led to downregulation of MMP-1, MMP-3 and MMP-9 transcripts. Whilst AA alone and Dex alone induced biomineralization of PDL cells, bFGF blocked the mineralization activity of the cells. In the Dex + bFGF group, more mineral nodules were noted when compared to AA alone and Dex alone groups. CONCLUSION: The addition of Dex to culture reversed bFGF-mediated inhibition of mineralization. Use of combined bFGF and Dex to regulate PDL cell function may be a good therapeutic option to obtain periodontal regeneration.
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Dexametasona/farmacología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Glucocorticoides/farmacología , Metaloproteinasas de la Matriz/efectos de los fármacos , Ligamento Periodontal/efectos de los fármacos , Inhibidores Tisulares de Metaloproteinasas/efectos de los fármacos , Calcificación Fisiológica/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Células Cultivadas , Colágeno Tipo I/efectos de los fármacos , Colágeno Tipo III/efectos de los fármacos , Colágeno Tipo X/efectos de los fármacos , ADN/efectos de los fármacos , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 3 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Ligamento Periodontal/citología , ARN Mensajero/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-1/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/efectos de los fármacosRESUMEN
AIM: To examine the effects of sonicated bacterial extracts (SBEs) from three related to periapical disease bacteria (Porphyromonas gingivalis, P. endodontalis and F. nucleatum) on the activation of matrix metalloproteinase (MMP-2) and the inactivation of tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2). METHODOLOGY: Each SBE was added to cultures of human periodontal ligament (PL) cells or HT1080 cells and their supernatants were analysed by zymography for MMP-2. Each SBE was added to PL cell cultures, and the amount of TIMP-1 was determined by ELISA. P. gingivalis SBE was incubated with HT1080 cell culture supernatants, and the amounts of TIMP-1 and TIMP-2 were determined by ELISA. Statistical analysis was performed with the paired Student's t-test. RESULTS: In extracts of PL cells that had been incubated in the presence of P. gingivalis SBE, one representing pro-MMP-2 (72 kDa) and a band corresponding to the active MMP-2 (66 kDa) were observed; but in the other extracts it was not detected. When HT1080 cells were treated with P. gingivalis SBE, the pro-MMPs was processed into 86- and 66-kDa fragments, but in the other extracts, the processing did not occur when the other SBEs were used. When PL cells were incubated with the same SBEs, the amount of TIMP-1 was markedly decreased (P < 0.01), but in the other extracts, it was not. The amounts of both TIMP-1 and TIMP-2 were decreased in a dose-dependent manner when HT1080 cell culture supernatant was incubated with P. gingivalis SBE. CONCLUSIONS: These findings suggest that P. gingivalis SBE may cause connective tissue to be destroyed, contributing to the process of periapical disease, by activating pro-MMP-2 as well as by inactivating TIMP-1 and TIMP-2.
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Metaloproteinasa 2 de la Matriz/metabolismo , Periodontitis Periapical/microbiología , Porphyromonas gingivalis/química , Inhibidor Tisular de Metaloproteinasa-1/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Línea Celular Tumoral , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Activación Enzimática , Precursores Enzimáticos/metabolismo , Matriz Extracelular/metabolismo , Fusobacterium nucleatum/química , Gelatinasas/metabolismo , Humanos , Periodontitis Periapical/enzimología , Ligamento Periodontal/citología , Porphyromonas endodontalis/química , SonicaciónRESUMEN
Matrix metalloproteinase-2 (MMP-2) is a lucrative therapeutic target as far as anticancer drug discovery is concerned. Overexpression of MMP-2 is found to facilitate tumour propagation through the involvement of vascular endothelial growth factor (VEGF). However, even after different techniques, finding a target-specific MMP-2 inhibitor with respectable pharmacodynamic properties is still a challenging task. Regression-dependent quantitative structure-activity relationship (QSAR) strategies might be among the possible drug design methods to explore the essential structural features that would be valuable to find a suitable MMP-2 inhibitor. In this paper, 72 molecules were explored using the PaDEL descriptors and stepwise multiple linear regression (S-MLR). The partial least squares (PLS) method was also used to create a viable statistical model with an acceptable metric related to these models. The final statistical models were formed with statistical parameters within acceptable range (r2 = 0.797, Q2 = 0.725 and r2pred = 0.643 for the MLR model, and r2 = 0.780, Q2 = 0.685 and r2pred = 0.666 for the PLS model). The models were analysed and compared with those already published on the same endpoint.
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Diseño de Fármacos , Ácidos Hidroxámicos/química , Relación Estructura-Actividad Cuantitativa , Sulfonamidas/química , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Análisis de los Mínimos Cuadrados , Modelos Lineales , Modelos MolecularesRESUMEN
Cardiomyocyte hypertrophy, a prevalent clinical condition is deeply associated with many physiological factors. The underlying mechanisms of cardiomyocyte hypertrophy are not yet fully understood. In this study, H9C2 cells were treated with genistein, miR-451 mimic, miR-451 inhibitor and isoproterenol for 24 h, to study the effect of genistein on isoproterenol-induced myocardial hypertrophy in vitro. Simultaneously, ICR mice were treated with genistein for 21 days to evaluate the effects of the phytochemical on isoproterenol-induced myocardial hypertrophy in vivo. Results showed that isoproterenol induced cardiac hypertrophy and down-regulated the expression of miR-451 and up-regulated miR-451's target gene TIMP2. Genistein increased the expression of miR-451 and inhibited the isoproterenol-induced cardiac hypertrophy. This study explored the function of genistein from the epigenetic level, suggesting that miR-451 may play a significant role in the genistein-assisted amelioration of isoproterenol-induced cardiac hypertrophy both in vitro and in vivo.
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Cardiomegalia/metabolismo , Genisteína/uso terapéutico , Isoproterenol/toxicidad , MicroARNs/biosíntesis , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidor Tisular de Metaloproteinasa-2/biosíntesis , Agonistas Adrenérgicos beta/toxicidad , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Femenino , Genisteína/farmacología , Células HeLa , Humanos , Ratones , Ratones Endogámicos ICR , MicroARNs/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidoresRESUMEN
BACKGROUND: Bone-derived mesenchymal stem cell (BMSC) transplantation has been reported to be effective for the treatment of ischemic heart disease, but whether BMSCs are the optimal cell type remains under debate. Increasing numbers of studies have shown that Nestin, an intermediate filament protein, is a potential marker for MSCs, which raises the question of whether Nestin+ cells in BMSCs may play a more crucial role in myocardial repair. METHODS: Nestin+ cells were isolated using flow cytometry by gating for CD45- Ter119- CD31- cells from the compact bone of Nestin-GFP transgenic mice, expressing GFP driven by the Nestin promoter. Colony-forming and proliferative curve assays were conducted to determine the proliferative capacity of these cells, while qRT-PCR was used to analyze the mRNA levels of relative chemokines and growth factors. Cardiac endothelial cell (CEC) recruitment was assessed via a transwell assay. Moreover, permanent ligation of the left anterior descending (LAD) coronary artery was performed to establish an acute myocardial infarction (AMI) mouse model. After cell transplantation, conventional echocardiography was conducted 1 and 4 weeks post-MI, and hearts were harvested for hematoxylin-and-eosin (HE) staining and immunofluorescence staining 1 week post-MI. Further evaluation of paracrine factor levels and administration of a neutralizing antibody (TIMP-1, TIMP-2, and CXCL12) or a CXCR4 antagonist (AMD3100) in MI hearts were performed to elucidate the mechanism involved in the chemotactic effect of Nestin+ BMSCs in vivo. RESULTS: Compared with Nestin- BMSCs, a greater proliferative capacity of Nestin+ BMSCs was observed, which further exhibited moderately high expression of chemokines instead of growth factors. More CEC recruitment in the Nestin+ BMSC-cocultured group was observed in vitro, while this effect was obviously abolished after treatment with neutralizing antibodies against TIMP-1, TIMP-2, or CXCL12, and more importantly, blocking the CXCL12/CXCR4 axis with a AMD3100 significantly reduced the chemotactic effect of Nestin+ BMSCs. After transplantation into mice exposed to myocardial infarction (MI), Nestin+ BMSC-treated mice showed significantly improved survival and left ventricular function compared with Nestin- BMSC-treated mice. Moreover, endogenous CECs were markedly increased, and chemokine levels were significantly higher, in the infarcted border zone with Nestin+ BMSC treatment. Meanwhile, neutralization of each TIMP-1, TIMP-2, or CXCL12 in vivo could reduce the left ventricular function at 1 and 4 weeks post-MI; importantly, the combined use of these three neutralizing antibodies could make a higher significance on cardiac function. Finally, blocking the CXCL12/CXCR4 axis with AMD3100 significantly reduced the left ventricular function and greatly inhibited Nestin+ BMSC-induced CEC chemotaxis in vivo. CONCLUSIONS: These results suggest that Nestin+ BMSC transplantation can improve cardiac function in an AMI model by recruiting resident CECs to the infarcted border region via the CXCL12/CXCR4 chemokine pathway. And we demonstrated that Nestin+BMSC-secreted TIMP-1/2 enhances CXCL12(SDF1α)/CXCR4 axis-driven migration of endogenous Sca-1+ endothelial cells in ischemic heart post-AMI. Taken together, our results show that Nestin is a useful marker for the identification of functional BMSCs and indicate that Nestin+ BMSCs could be a better therapeutic candidate for cardiac repair.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Infarto del Miocardio/terapia , Nestina/genética , Animales , Anticuerpos Neutralizantes/farmacología , Bencilaminas , Huesos/citología , Proliferación Celular/efectos de los fármacos , Quimiocina CXCL12/antagonistas & inhibidores , Quimiocina CXCL12/genética , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Ciclamas , Células Endoteliales/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Transgénicos , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , ARN Mensajero/genética , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Inhibidor Tisular de Metaloproteinasa-1/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-2/genéticaRESUMEN
Ischemic stroke (IS) is an acute cerebral event characterized by a high incidence rate, high disability rate as well as a high mortality. More recently, accumulative literature has provided evidence highlighting the role played by microRNAs (miRs) in the development of neurons. Hence, the aim of the present study was to investigate the neuroprotective role of miR-410 in IS. Microarray-based gene expression profiling of AMI was conducted in order to identify differentially expressed genes (DEGs) and the corresponding miRs regulating these genes. IS models were established to assess neurology on a scoring basis. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) were all subsequently assessed. The functional role of miR-410 in IS was determined based on ectopic expression, knockdown and reporter assay experiments in hippocampal neurons. The expressions of microRNA-410, TIMP2, ERK, p38MAPK, JNK were all examined accordingly. The survival rate was assessed by MTT assay, and cell cycle and apoptosis by flow cytometry. After the loss of hippocampal neurons, infarct size as well as oxidative stress injury had been detected, microarray technology revealed that TIMP2 was differentially expressed in IS and that miR-410 regulated TIMP2. Initial observations revealed elevated levels of TIMP2 expression and MDA activity, in addition to evidence obtained indicated that the MAPK pathway had been activated along with decreased SOD, GSH-Px activity and miR-410 expression in IS mice. Ectopic expression of miR-410 was observed to inactivate the MAPK pathway, TIMP2 expression and hippocampal neuron apoptosis, while elevated hippocampal neuron survival rates and cell cycle entry were detected. Furthermore, TIMP2 as a direct target gene of miR-410, was determined to be negatively regulated by miR-410, while the MAPK pathway was found to be inhibited following TIMP2 knockdown. Our results revealed that the overexpression of miR-410 could ameliorate hippocampal neuron loss, reduce infarct size and oxidative stress injury in IS mice. Taken together, the key evidence of the current study elucidated the distinct nature of the inhibitory effect on IS as a result of overexpressed miR-410 whereby the conferral of neuroprotection was observed in oxidative stress-induced apoptosis post IS through the TIMP2-dependent repression of the MAPK pathway in mice.
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Sistema de Señalización de MAP Quinasas , MicroARNs/metabolismo , Estrés Oxidativo/fisiología , Accidente Cerebrovascular/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/antagonistas & inhibidores , Animales , Apoptosis/genética , Apoptosis/fisiología , Isquemia Encefálica/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Masculino , Malondialdehído/metabolismo , Ratones , MicroARNs/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuroprotección/fisiología , Estrés Oxidativo/genética , Daño por Reperfusión/metabolismo , Superóxido Dismutasa/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
BACKGROUND: Matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) trigger the signal cascade instigating cardiac remodeling and fibrosis, which lead to changes of repolarization variables. We investigate the influence of MMP9-1562 C/T and TIMP2-418 G/C gene polymorphisms on repolarization parameters including QT dispersion (QTd) and the peak and the end of the T wave interval (Tpe) in a prospective cohort. METHODS: Of 1500 people screened, 106 elderly Chinese without organic heart disease were recruited and received electrocardiography at the baseline, second and 4th year follow-ups. The QTc (corrected QT), QTd, QTc dispersion (QTcd) and Tpe were manually calculated. RESULTS: Age was 72.7+/-4.1 y (range 62-81 y). QTd, QTcd and Tpe were significantly prolonged (all p <0.001 at the 2nd and 4th year). At the 4th year the magnitude of QTd prolongation but not Tpe was significantly higher in subjects carrying the TIMP2 C-allele than non C-allele carriers (p=0.033) as well as QTcd (p=0.010). This association was still significant in multivariate analyses (p=0.012 and p=0.003 for QTd and QTcd, respectively) but not in MMP9 genotype. CONCLUSIONS: The elderly Chinese with TIMP2 C-allele have higher magnitude of QTd and QTcd prolongation.