Rodriguez, J.A. (José Antonio)
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- Association between matrix metalloproteinase-10 concentration and smoking in individuals without cardiovascular disease(Elsevier, 2008) Paramo, J.A. (José Antonio); Beloqui, O. (Óscar); Diez-Martinez, J. (Javier); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio)INTRODUCTION AND OBJECTIVES: Smoking is an important cardiovascular risk factor whose underlying mechanism is incompletely understood. However, it has been suggested that alterations in the balance between synthesis and degradation of the extracellular matrix (ECM) may play a role. The aim of this study was to determine whether there is an independent association between smoking and the concentration of circulating metalloproteinases (MMPs) in individuals without cardiovascular disease. METHODS: Metabolic parameters, the carotid intima-media thickness (IMT), inflammatory markers (fibrinogen, C-reactive protein and interleukin-6), markers of endothelial damage (e.g., von Willebrand factor), and the concentration of MMP-1, -9 and -10 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in 400 asymptomatic individuals with cardiovascular risk factors. Subjects were divided into non-smokers (n=195), smokers (n=118) and former smokers (n=87). In addition, global cardiovascular risk was determined from PROCAM and REGICOR scores. RESULTS: Both MMP-1 and MMP-10 concentrations were significantly higher in smokers than non-smokers (P< .05 and P< .001, respectively), though there was no difference in the levels of MMP-9, TIMP-1, IMT and other inflammatory parameters. There were positive correlations between the MMP-10 concentration and PROCAM and REGICOR scores (P< .001). Multivariate analysis showed that there was still an association between smoking and the MMP-10 concentration after adjustment for age, sex and other cardiovascular risk factors (P< .001). Multiple regression analysis showed that smoking accounted for 28% of the variability in the MMP-10 concentration. CONCLUSIONS: There was an independent association between smoking and the MMP-10 concentration in asymptomatic individuals. This relationship between MMP-10 and the ECM may indicate a mechanism through which this MMP contributes to smoking-related atherosclerosis.
- Matrix metalloproteinase-10 effectively reduces infarct size in experimental stroke by enhancing fibrinolysis via a thrombin-activatable fibrinolysis inhibitor-mediated mechanism(Lippincott, Williams & Wilkins, 2011) Parks, W.C. (William C.); Paramo, J.A. (José Antonio); Purroy, A. (A.); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Barrenetxe, J. (Jaione); Serrano, R. (Rosario); Martinez-de-Lizarrondo, S. (Sara); Orset, C. (C.); Angles-Cano, E. (Eduardo); Vivien, D. (D.); Birkland, T.P. (T.P.)BACKGROUND: The fibrinolytic and matrix metalloproteinase (MMP) systems cooperate in thrombus dissolution and extracellular matrix proteolysis. The plasminogen/plasmin system activates MMPs, and some MMPs have been involved in the dissolution of fibrin by targeting fibrin(ogen) directly or by collaborating with plasmin. MMP-10 has been implicated in inflammatory/thrombotic processes and vascular integrity, but whether MMP-10 could have a profibrinolytic effect and represent a promising thrombolytic agent is unknown. METHODS AND RESULTS: The effect of MMP-10 on fibrinolysis was studied in vitro and in vivo, in MMP-10-null mice (Mmp10(-/-)), with the use of 2 different murine models of arterial thrombosis: laser-induced carotid injury and ischemic stroke. In vitro, we showed that MMP-10 was capable of enhancing tissue plasminogen activator-induced fibrinolysis via a thrombin-activatable fibrinolysis inhibitor inactivation-mediated mechanism. In vivo, delayed fibrinolysis observed after photochemical carotid injury in Mmp10(-/-) mice was reversed by active recombinant human MMP-10. In a thrombin-induced stroke model, the reperfusion and the infarct size in sham or tissue plasminogen activator-treated animals were severely impaired in Mmp10(-/-) mice. In this model, administration of active MMP-10 to wild-type animals significantly reduced blood reperfusion time and infarct size to the same extent as tissue plasminogen activator and was associated with shorter bleeding time and no intracranial hemorrhage. This effect was not observed in thrombin-activatable fibrinolysis inhibitor-deficient mice, suggesting thrombin-activatable fibrinolysis inhibitor inactivation as one of the mechanisms involved in the MMP-10 profibrinolytic effect. CONCLUSIONS: A novel profibrinolytic role for MMP-10 in experimental ischemic stroke is described, opening new pathways for innovative fibrinolytic strategies in arterial thrombosis.
- Hyperhomocysteinemia in liver cirrhosis: mechanisms and role in vascular and hepatic fibrosis(American Heart Association, 2001) Martin-Duce, A. (Antonio); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Avila, M.A. (Matías Antonio); Rodriguez, J.A. (José Antonio); Ruiz Garcia-Trevijano, E. (Elena); Caballeria, J. (Juan); Mato, J.M. (José María); Arias, R. (Roberto)Numerous clinical and epidemiological studies have identified elevated homocysteine levels in plasma as a risk factor for atherosclerotic vascular disease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions leading to vitamin B(6), B(12), or folate deficiencies; or chronic alcohol consumption. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver. Impaired liver function leads to altered methionine and homocysteine metabolism; however, the molecular basis for such alterations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the present work, we have examined the expression of the main enzymes involved in methionine and homocysteine metabolism, along with the plasma levels of methionine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homocysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have observed a marked reduction in the expression of the main genes involved in homocysteine metabolism in liver cirrhosis. In addition, we have identified the tissue inhibitor of metalloproteinases-1 and alpha1(I)procollagen to be upregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocysteine levels in the development of liver fibrosis.
- Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice(Wiley, 2021) Calvo, I.A. (Isabel A.); Granero-Moltó, F. (Froilán); Paramo, J.A. (José Antonio); Ripalda-Cemboráin, P. (Purificación); Montiel-Terrón, V. (Verónica); Aldazabal, J. (Javier); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Lopez, T. (Tania); Valdés-Fernández, J. (José); Muiños-López, E. (Emma); Romero-Torrecilla, J.A. (Juan Antonio); Prosper-Cardoso, F. (Felipe); Saez, B. (Borja)The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion
- Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study(2020) Gállego-Culleré, J. (Jaime); Irimia, P. (Pablo); Domínguez-Echávarri, P.D. (Pablo Daniel); Moreno-Ajona, D. (David); Rodriguez, J.A. (José Antonio); Muñoz, R. (Roberto); Fernandez-Alonso, L. (Leopoldo); Garcia-Velloso, M. J. (María José); López-Fidalgo, J. (Jesús); Grochowitz, L. (Lukasz); Martinez-Vila, E. (Eduardo)Background: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. Methods: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDGPET/CT focusing on several territories’ vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. Results: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. Conclusions: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory.
- The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis(2013) Martin, M. (Mar); Paramo, J.A. (José Antonio); Borreguero-Leon, J.M. (Juan María); Lorente, L. (Leonardo); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Blanquer, J. (José); Plasencia, F. (Fátima); Jimenez, A. (Alejandro); Salido, E. (Eduardo); Sole-Violan, J. (Jordi); Díaz, C. (César); Labarta, L. (Lorenzo)Introduction: Previous studies have found higher circulating levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in nonsurviving septic patients than in surviving septic patients, and an association between the 372 T/C genetic polymorphism of TIMP-1 and the risk of developing certain diseases. However, the relationship between genetic polymorphisms of TIMP-1, circulating TIMP-1 levels and survival in patients with severe sepsis has not been examined, and this was the objective of the study. Methods: This multicentre, prospective, observational study was carried out in six Spanish ICUs. We determined the 372 T/C genetic polymorphism of TIMP-1 (rs4898), serum levels of TIMP-1, matrix metalloproteinase (MMP)-9, MMP-10, TNFa, IL-10 and plasma plasminogen activator inhibitor-1 (PAI-1). Survival at 30 days from ICU admission was the endpoint assessed. The association between continuous variables was carried out using Spearman’s rank correlation coefficient or Spearman’s rho coefficient. Multivariate logistic regression analysis was applied to determine the association between the 372 T/C genetic polymorphism and survival 30 days from ICU admission. Results: Of 275 patients with severe sepsis, 80 had genotype CC, 55 had genotype CT and 140 had genotype TT of the 372 T/C genetic polymorphism of TIMP-1. Patients with the T allele showed higher serum levels of TIMP-1 than patients without the T allele (P = 0.004). Multiple logistic regression analysis showed that the T allele was associated with higher mortality at 30 days (odds ratio = 2.08; 95% confidence interval = 1.06 to 4.09; P = 0.03). Survival analysis showed that patients with the T allele presented lower 30-day survival than patients without the T allele (c2 = 5.77; P = 0.016). We found an association between TIMP-1 levels and levels of MMP-9 (r = -0.19; P = 0.002), MMP-10 (r = 0.55; P <0.001), TNFa (r = 0.56; P <0.001), IL-10 (r = 0.48; P <0.001) and PAI-1 (r = 0.49; P <0.001). Conclusion: The novel findings of our study are that septic patients with the T allele in the 372 T/C genetic polymorphism of TIMP-1 showed higher serum TIMP-1 levels and lower survival rate. The determination of the 372 T/C genetic polymorphism of TIMP-1 thus has prognostic implications and could help in the selection of patients who may benefit from modulation of the MMP/TIMP balance.
- Combined sustained release of BMP2 and MMP10 accelerates bone formation and mineralization of calvaria critical size defect in mice(Taylor & Francis, 2018) Arnau, M.R. (María Rosa); Reyes, R. (Ricardo); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Delgado, A. (Araceli); Évora, C. (Carmen)The effect of dual delivery of bone morphogenetic protein-2 (BMP-2) and matrix metalloproteinase 10 (MMP10) on bone regeneration was investigated in a murine model of calvarial critical-size defect, hypothesizing that it would result in an enhanced bone formation. Critical-size calvarial defects (4 mm diameter) were created in mice and PLGA microspheres preloaded with either BMP-2, MMP10 or a microsphere combination of both were transplanted into defect sites at different doses. Empty microspheres were used as the negative control. Encapsulation efficiency was assessed and in vivo release kinetics of BMP-2 and MMP10 were examined over 14 days. Histological analyses were used to analyze bone formation after four and eight weeks. Combination with MMP10 (30 ng) significantly enhanced BMP-2 (600 ng)-mediated osteogenesis, as confirmed by the increase in percentage of bone fill (p < .05) at four weeks. Moreover, it also increased mineral apposition rate (p < .05), measured by double labeling with tetracycline and calceine. MMP10 accelerates bone repair by enhancing BMP-2- promoted bone healing and improving the mineralization rate. In conclusion combination of MMP10 and BMP-2 may become a promising strategy for repair and regeneration of bone defects.
- CM-352 Efficacy in a mouse model of anticoagulant-associated intracranial hemorrhage(Thieme, 2022) Navarro-Oviedo, M. (Manuel); Paramo, J.A. (José Antonio); Pineda-Lucena, A. (Antonio); Zandio, B. (Beatriz); Hermida, J. (José); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Muñoz, R. (Roberto); Oyarzabal, J. (Julen); Lecumberri, R. (Ramón); Roncal, C. (Carmen); Marta-Enguita, J. (Juan)Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.
- Metalloproteases, vascular remodeling and atherothrombotic syndromes(Elsevier España, 2007) Paramo, J.A. (José Antonio); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio)Defects in the synthesis and breakdown of the extracellular matrix (ECM) are now seen as key processes in the development of atherosclerosis and its thrombotic complications. Correlations have been observed between circulating levels of ECM biomarkers and the clinical manifestations of and risk factors for atherosclerosis. Several matrix metalloproteinases (MMPs), endopeptidases that can degrade the ECM, such as MMP-9 and MMP-10, play important roles in the pathophysiology of atherothrombosis and contribute to the expansion of abdominal aortic aneurysms. Moreover, they may also be useful biomarkers of atherosclerotic risk and serve as predictors of coronary and cerebrovascular disease recurrence. Although at present the effect of tissue inhibitors of MMPs (TIMPs) on cardiovascular disease prognosis is still uncertain, the ECM could be a promising therapeutic target in atherothrombotic disease, and several MMP inhibitors are currently undergoing clinical trials.
- Photodynamic nasal SARS-CoV-2 decolonization shortens infectivity and influences specific T-Cell responses.(Frontiers, 2023) Moreno-Galarraga, L. (Laura); Martin-Navarro, L. (Loreto); González-Aseguinolaza, G. (Gloria); Muñoz-Rodríguez, N. (Natalia); Pineda-Lucena, A. (Antonio); Olagüe, C. (Cristina); Pina-Sanchez, M. (Manuel); Camps, G. (Gracian); Rua, M. (Marta); Smerdou, C. (Cristian); Pozo, J.L. (José Luis) del; Pozuelo, M. (Marta); Zuaznabar, J. (Jon); Rodriguez, J.A. (José Antonio); Carmona-Torre, F. (Francisco de A.); Fernandez-Montero, A. (Alejandro); Zazpe, J. (Jon); Reina, G. (Gabriel); Kolenda, J. (Jack); Marchese, F.P. (Francesco P.); Quiroga, J. (Jorge); Martínez-Fernández, M. (Maria); Argemí, J. (Josepmaria); Pastrana, M. (Marta); Maestro, S. (Sheila)Background: The main objective was to evaluate the efficacy of intranasal photodynamic therapy (PDT) in SARS-CoV-2 mildly symptomatic carriers on decreasing the infectivity period. SARS-CoV-2-specific immune-stimulating effects and safety were also analysed. Methods: We performed a randomized, placebo-controlled, clinical trial in a tertiary hospital (NCT05184205). Patients with a positive SARS-CoV-2 PCR in the last 48 hours were recruited and aleatorily assigned to PDT or placebo. Patients with pneumonia were excluded. Participants and investigators were masked to group assignment. The primary outcome was the reduction in in vitro infectivity of nasopharyngeal samples at days 3 and 7. Additional outcomes included safety assessment and quantification of humoral and T-cell immune-responses. Findings: Patients were recruited between December 2021 and February 2022. Most were previously healthy adults vaccinated against COVID-19 and most carried Omicron variant. 38 patients were assigned to placebo and 37 to PDT. Intranasal PDT reduced infectivity at day 3 post-treatment when compared to placebo with a b-coefficient of -812.2 (CI95%= -478660 – -1.3, p<0.05) infectivity arbitrary units. The probability of becoming PCR negative (ct>34) at day 7 was higher on the PDT-group, with an OR of 0.15 (CI95%=0.04-0.58). There was a decay in anti-Spike titre and specific SARS-CoV-2 T cell immunity in the placebo group 10 and 20 weeks after infection, but not in the PDT-group. No serious adverse events were reported. Interpretation: Intranasal-PDT is safe in pauci-symptomatic COVID-19 patients, it reduces SARS-CoV-2 infectivity and decelerates the decline SARS-CoV-2 specific immune-responses.