Raquel F Gerlach

University of São Paulo, San Paulo, São Paulo, Brazil

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Publications (130)372.75 Total impact

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    ABSTRACT: Hypertension induces left ventricular hypertrophy (LVH) by mechanisms involving oxidative stress and imbalanced cardiac matrix metalloproteinase (MMP) activity. We hypothesized that β1-adrenergic receptor blockers with antioxidant properties (nebivolol) could reverse hypertension-induced LVH more effectively than conventional β1-blockers (metoprolol) when used at doses that exert similar antihypertensive effects. Two kidney one clip (2K1C) hypertension was induced in male Wistar rats. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10mg.kg(-1).day(-1)) or metoprolol (20mg.kg(-1).day(-1)) for four weeks. Systolic blood pressure (SBP) was monitored weekly by tail-cuff plethysmography. LV structural changes and fibrosis were studied in hematoxylin/eosin and picrosirius stained sections, respectively. Cardiac MMP levels and activity were determined by in situ zymography, gel zymography, and by immunofluorescence. Dihydroethidium (DHE) and lucigenin-derived chemiluminescence assays were used to assess cardiac reactive oxygen species production. Nitrotyrosine levels were determined in LV samples by immunohistochemistry. green fluorescence, and was evaluated using the ImageJ software. Cardiac protein kinase B/Akt (AKT) phosphorilation state was assessed by Western blot. Both treatments exerted very similar antihypertensive effects. Both beta-blockers exerted similar antihypertensive effects and attenuated hypertension-induced cardiac remodeling. Both drugs reduced myocyte hypertrophy and collagen deposition in 2K1C rats. Those effects were associated with lower cardiac ROS and nitrotyrosine levels, and attenuation of hypertension-induced increases in cardiac MMP-2 levels and in situ gelatinolytic activity after treatment with both β-blockers. While hypertension increased AKT phosphorilation, no effects were found with β-blockers. In conclusion, we found evidence that two β1-blockers with different properties attenuate hypertension-induced LV hypertrophy and cardiac collagen deposition in association with significant cardiac antioxidant effects and MMP-2 dowregulation, thus suggesting a critical role for β1-adrenergic receptors in mediating those effects. Nebivolol is not superior to metoprolol, at least with respect to their capacity to reverse hypertension-induced LVH.
    Free radical biology & medicine. 06/2014;
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    ABSTRACT: This MiniReview describes the essential biochemical and molecular aspects of matrix metalloproteinases (MMPs) and briefly discusses how they engage in different diseases, with particular emphasis on cardiovascular diseases. There is compelling scientific evidence that many MMPs, especially MMP-2, play important roles in the development of cardiovascular diseases; inhibition of these enzymes is beneficial to many cardiovascular conditions, sometimes precluding or postponing end-organ damage and fatal outcomes. Conducting comprehensive discussions and further studies on how MMPs participate in cardiovascular diseases is important, because inhibition of these enzymes may be an alternative or an adjuvant for current cardiovascular disease therapy.This article is protected by copyright. All rights reserved.
    Basic & Clinical Pharmacology & Toxicology 06/2014; · 2.18 Impact Factor
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    ABSTRACT: Shed teeth have been proposed as trace element biomarkers. This study determined variations in the spatial distribution of Ca, K, Zn, Pb, Mn, Cu, and Sr in four anatomical locations: superficial enamel (SE, 0-10 μm), subsuperficial enamel (SSE, 10-30 μm), primary dentine (PD), and secondary dentine (SD). Five primary incisors were analyzed by micro Synchrotron Radiation X-Ray Fluorescence (μ-SRXRF). Two teeth had low concentrations of lead in the SE (< 250 μg/g), while three contained very high lead concentrations in the SE (> 2,000 μg/g). Teeth were sliced, and five spot measurements (20 μm beam diameter) were accomplished in each location. The data are shown as absolute values and as the ratio between the different elements and Ca. The distribution of K was close to that of Ca. Zn was the third most abundant element, with the highest levels being found in the SE and SD and low levels detected in the PD. Increasing Sr levels were found progressing from the enamel to the dentine, with the highest levels being found in the SD, a distribution that was unique. Pb, Mn, and Cu exhibited a similar trend, with higher signals for these elements detected in the SE. This study provides preliminary data on the heterogeneous distribution of different elements in the tooth, highlighting the importance of the first 10 μm of the SE for determination of some elements, such as Zn, Pb, Mn, and Cu.
    Journal of Trace Elements in Medicine and Biology 01/2014; · 1.96 Impact Factor
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    ABSTRACT: Although disorders of the stomatognathic system are common, the mechanisms involved are unknown. Our objective was to study the changes in the masseter muscles after unilateral exodontia. Molar extraction was performed on Wistar rats (left side), and the animals were sacrificed after either 14 or 26 days. The masseter muscle was processed for histological analysis, conventional and in situ zymography, and immunohistochemistry. The morphological analysis showed unique and specific characteristics for the experimental group. By conventional zymography no significant values of 72 kDa MMP-2 (P < 0.05) were found in both of the sides of masseter muscle after 14 and 26 days of unilateral extraction. The in situ zymography showed gelatinolytic activity on all deep masseter muscles, with significant increase on the contralateral side after 14 and 26 days (P < 0.05). The immunohistochemistry demonstrated greater expression of MMP-2 than MMP-9 and MMP-14 in all masseter muscles and there were few differences in the staining of 4 TIMPs. This knowledge about morphology and molecular masticatory muscle remodeling following environmental interventions can be used to develop clinically successful treatments.
    BioMed Research International 01/2014; 2014:563463. · 2.71 Impact Factor
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    ABSTRACT: Matrix metalloproteinase‐2 (MMP‐2) shares structural similarities with the angiotensin‐converting enzyme (ACE). ACE inhibitors have been described to inhibit MMP‐2, but this inhibitory potential was not shown using a highly purified MMP‐2. This study aimed to investigate the inhibitory potential of captopril and lisinopril regarding MMP‐2 activity. The first objective was to test the potential of captopril to change the pH of the buffer solution. The second objective was to test the direct inhibitory effect of captopril and lisinopril on plasma MMP‐2 and on recombinant human MMP‐2 (rhMMP‐2). The in vitro activity assays included gelatin zymography and a fluorimetric assay. Captopril solubilization significantly decreased the pH of the 50 mM Tris buffer solution at the following concentrations: 2 mM (p p p p p p p in vivo after drug administration. We also discuss possible pitfalls for gelatinase inhibitory assays (besides the obvious pH problem already cited). In conclusion, this study's data show that captopril and lisinopril did not inhibit MMP‐2 directly at the concentrations reached in vivo.
    Basic &amp Clinical Pharmacology &amp Toxicology 01/2014; 114(3). · 2.12 Impact Factor
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    ABSTRACT: The aim of this study was to see whether there would be differences in whole blood versus tibia lead concentrations over time in growing rats prenatally. Lead was given in the drinking water at 30 mg/L from the time the dams were pregnant until offspring was 28- or 60-day-old. Concentrations of lead were measured in whole blood and in tibia after 28 (28D) and 60 days (60D) in control (C) and in lead-exposed animals (Pb). Lead measurements were made by GF-AAS. There was no significant difference (P > 0.05) in the concentration of whole blood lead between Pb-28D (8.0 ± 1.1 μ g/dL) and Pb-60D (7.2 ± 0.89 μ g/dL), while both significantly varied (P < 0.01) from controls (0.2 μ g/dL). Bone lead concentrations significantly varied between the Pb-28D (8.02 ± 1.12 μ g/g) and the Pb-60D (43.3 ± 13.26 μ g/g) lead-exposed groups (P < 0.01), while those exposed groups were also significantly higher (P < 0.0001) than the 28D and 60D control groups (Pb < 1 μ g/g). The Pb-60D group showed a 25% decrease in tibia mass as compared to the respective control. The five times higher amount of lead found in the bone of older animals (Pb-60D versus Pb-28D), which reinforces the importance of using bone lead as an exposure biomarker.
    BioMed research international. 01/2014; 2014:571065.
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    ABSTRACT: Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 μg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ~185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT.
    Journal of Cellular and Molecular Medicine 11/2013; · 4.75 Impact Factor
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    ABSTRACT: Increased matrix metalloproteinase (MMP) levels are involved in vascular remodeling of hypertension. In this study, we hypothesized that doxycycline (a MMP inhibitor) could exert antioxidant effects, reverse establish vascular remodeling, and lower blood pressure in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats received either doxycycline at 30 mg/kg/day by gavage or vehicle. Systolic blood pressure (SBP) was assessed weekly by tail cuff. After 5 weeks of treatment, morphologic changes in the aortic wall were studied in hematoxylin/eosin sections. MMP activity and expression were determined by in situ zymography using DQ gelatin and immunofluorescence for MMP-2. Dihydroethidium was used to evaluate aortic reactive oxygen species (ROS) production by fluorescence microscopy. Doxycycline reduced SBP by 25 mmHg. However, the antihypertensive effects were not associated with significant reversal of hypertension-induced vascular hypertrophy. SHR showed increased aortic MMP-2 levels which co-localized with higher aortic MMP activity and ROS levels, and all those biochemical alterations associated with hypertension were blunted by treatment with doxycycline. These results show that MMP inhibition with doxycycline in SHR with established hypertension resulted in antioxidant effects, lower gelatinolytic activity, and antihypertensive effects which were not associated with reversal of hypertension-induced vascular remodeling.
    Molecular and Cellular Biochemistry 10/2013; · 2.33 Impact Factor
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    ABSTRACT: Different IL4 haplotypes were associated to susceptibility to/or protection against chronic periodontitis (CP). The aim of this study was to investigate if individuals carrying different haplotypes would present differences in clinical periodontal parameters and in the IL-4 levels at baseline, 45 and 90 days after non-surgical periodontal therapy. Sixty-two patients were subdivided: genetically protected without CP (PH), genetically protected with CP (PCP), genetically susceptible with CP (SCP), genetically susceptible without CP (healthy) (SH). Clinical examination and gingival crevicular fluid (GCF) collection were performed for all patients, and IL-4 levels were measured by ELISA. At baseline, higher values for plaque index (PI, p=0.013), gingival index (GI, p=0.005) were observed for the SCP group in comparison to the PCP group but not after the completion of periodontal therapy. Forty-five and 90 days after the non-surgical therapy, PCP demonstrated significantly higher IL-4 levels than the SCP (p=0.000002). Correlation analysis showed different results between clinical parameters and IL-4 production or GCF volume for groups with different genetic loads. The IL4 gene which was previously associated with susceptibility to CP was related with differences in the IL-4 protein levels in the GCF. However, independent of genetic carriage, individuals responded similarly to this therapy.
    Human immunology 09/2013; · 2.55 Impact Factor
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    ABSTRACT: Nebivolol and metoprolol are β1-adrenergic receptor blockers with different properties. We hypothesized that nebivolol, but not metoprolol, could attenuate prooxidant and profibrotic mechanisms of hypertension and therefore protect against the vascular remodeling associated with hypertension. Hypertension was induced in male Wistar rats by clipping the left renal artery. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10mg. mg.kg(-1).day(-1)) or metoprolol (20mg.kg(-1).day(-1)) for four weeks. Systolic blood pressure was monitored weekly. Morphologic changes in the aortic wall were studied in hematoxylin/eosin and picrosirius red sections. Aortic NAD(P)H activity and superoxide production were evaluated by luminescence and dihydroethidium, respectively, and TBARS levels were measured in plasma. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. TGF-β levels and p-ERK 1/2 expression were determined by immunofluorescence and western blotting, respectively. Matrix metalloproteinase (MMP) activity and expression were determined by in situ zymography, gel zymography, western blotting and immunofluorescence, and TIMP-1 was assessed by immunohistochemistry. Both β1-receptor antagonists exerted very similar antihypertensive effects. However, while metoprolol had no significant effects, nebivolol significantly attenuated vascular remodeling and collagen deposition associated with hypertension. Moreover, nebivolol, but not metoprolol, attenuated hypertension-induced increases in aortic NAD(P)H oxidase activity, superoxide production, TBARS concentrations, nitrotyrosine levels, TGF-β upregulation and MMP-2 and -9 expression/activity. No effects on p-ERK 1/2 and TIMP-1 expression were found. These results show for the first time that nebivolol, but not metoprolol, attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMP-2 and MMP-9, which promote vascular remodeling in hypertension.
    Free Radical Biology & Medicine 06/2013; · 5.27 Impact Factor
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    ABSTRACT: BACKGROUND: Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases with an important role in physiological and pathological remodeling. Their activity is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). Excess MMPs and myeloperoxidase (MPO) activity has been associated with loss of tooth supporting tissues in periodontal disease (PD). We investigate the changes in salivary MMP-8, MMP-9, TIMP-1, TIMP-2, and MPO concentrations during PD treatment and compare results with plasma levels. METHODS: MMP-8, MMP-9, TIMP-1 and TIMP-2 were analyzed by ELISA. Gelatinolytic activity of MMP-9 forms were determined by zymography, and the MPO activity was determined by colorimetric assay. RESULTS: Subjects were divided into 2 groups: PD and control, which were further divided into 2 subgroups each, namely PD before (PB) and after 3months (PA) of non-surgical periodontal therapy, and healthy volunteers at baseline (CB) and 3months after baseline (CA). Subgroup PA presented lower gelatinolytic activity and MMP-8 and TIMP-2 concentrations in the saliva compared with PB (p<0.05). MPO activity was higher in PB compared with CB (p<0.05). There were significant correlations between the gelatinolytic activity of the saliva and MMP-8 and MMP-9 plasma levels. There was significant correlation between plasma and saliva TIMP-2 levels. CONCLUSION: These results suggest attenuation of some inflammatory markers in the saliva and plasma after PD treatment. Moreover, correlations between salivary and plasma levels exist for some of these markers.
    Clinica chimica acta; international journal of clinical chemistry 03/2013; · 2.54 Impact Factor
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    ABSTRACT: Cardiovascular diseases involve critical mechanisms including impaired nitric oxide (NO) levels and abnormal matrix metalloproteinase (MMP) activity. While NO downregulates MMP expression in some cell types, no previous study has examined whether NO downregulates MMP levels in endothelial cells. We hypothesized that NO donors could attenuate MMP-9 production by human umbilical vein endothelial cells (HUVECs) as a result of less NFκB activation or cyclic GMP (cGMP)-mediated mechanisms. We studied the effects of DetaNONOate (10-400 μM) or SNAP (50-400 μM) on phorbol 12-myristate 13-acetate (PMA; 10 nM)-induced increases in MMP-9 activity (by gel zymography) or concentrations (by ELISA) as well as on a tissue inhibitor of MMPs' (TIMP)-1 concentrations (by ELISA) in the conditioned medium of HUVECs incubated for 24 h with these drugs. We also examined whether the irreversible inhibitor of soluble guanylyl cyclase ODQ modified the effects of SNAP or whether 8-bromo-cGMP (a cell-permeable analog of cGMP) influenced PMA-induced effects on MMP-9 expression. Total and phospho-NFκB p65 concentrations were measured in HUVEC lysates to assess NFκB activation. Both NO donors attenuated PMA-induced increases in MMP-9 activity and concentrations without significantly affecting TIMP-1 concentrations. This effect was not modified by ODQ, and 8-bromo-cGMP did not affect MMP-9 concentrations. While PMA increased phospho-NFκB p65 concentrations, SNAP had no influence on this effect. In conclusion, this study shows that NO donors may attenuate imbalanced MMP expression and activity in endothelial cells independent of cGMP- or NFκB-mediated mechanisms. Our results may offer an important pharmacological strategy to approach cardiovascular diseases.
    Molecular and Cellular Biochemistry 03/2013; · 2.33 Impact Factor
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    ABSTRACT: Nitric oxide (NO)-derived metabolites including the anion nitrite can recycle back to NO and thus complement NO formation independent of NO synthases. While nitrite is as a major vascular storage pool and source of NO, little is known about drugs that increase tissue nitrite concentrations. This study examined the effects of atorvastatin or sildenafil, or the combination, on vascular nitrite concentrations and on endothelial dysfunction in the 2 kidney-1 clip (2K1C) hypertension model. Sham-operated or 2K1C hypertensive rats were treated with vehicle, atorvastatin (50 mg/Kg), sildenafil (45 mg/Kg), or both for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Nitrite concentrations were assessed in the aortas and in plasma samples by ozone-based reductive chemiluminescence assay. Aortic rings were isolated to assess endothelium-dependent and independent relaxation. Aortic NADPH activity and ROS production were evaluated by luminescence and dihydroethidium, respectively, and plasma TBARS levels were measured. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. Atorvastatin and sildenafil, alone or combined, significantly lowered SBP by approximately 40 mmHg. Atorvastatin significantly increased vascular nitrite levels by 70% in hypertensive rats, whereas sildenafil had no effects. Both drugs significantly improved the vascular function, and decreased vascular NADPH activity, ROS, and nitrotyrosine levels. Lower plasma TBARS concentrations were found with both treatments. The combination of drugs showed no improved responses compared to each drug alone. These findings show evidence that atorvastatin, but not sildenafil, increases vascular NO stores, although both drugs exert antioxidant effects, improve endothelial function, and lower blood pressure in 2K1C hypertension.
    Redox biology. 01/2013; 1(1):578-85.
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    ABSTRACT: PURPOSE: Angiotensin-converting enzyme inhibitors (ACEi) may downregulate matrix metalloproteinases (MMPs). We examined whether enalapril affects MMP-2, MMP-8, and MMP-9 levels and activity, and their endogenous inhibitors (tissue inhibitors of MMPs, TIMP-1 and TIMP-2) levels in hypertensive patients. Moreover, we assessed the effects of enalaprilat on MMP-9 and TIMP-1 secretion by human endothelial cells (HUVECs). METHODS: Thirty-eight hypertensive patients received enalapril for 8 weeks and were compared with thirty-eight normotensive controls. Blood samples were collected at baseline and after treatment. Plasma ACE activity was determined by a fluorimetric assay. Plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA and gelatin zymography. A fluorogenic peptide cleavage assay was used to measure MMP activity. HUVECs cells were stimulated by phorbol-12-myristate-13-acetate (PMA) and the effects of enalaprilat (10(-10) to 10(-6) M) on MMP-9 and TIMP-1 levels were determined. RESULTS: Enalapril decreased blood pressure and ACE activity in hypertensive patients (P < 0.05), but had no effects on plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 levels, or MMP activity. Enalaprilat had no effects on PMA-induced increases in MMP-9 and TIMP-1 secretion by HUVECs or on MMP activity. CONCLUSIONS: We show consistent evidence, both in vivo and in vitro, that enalapril does not affect MMPs and TIMPs levels in hypertensive patients.
    Cardiovascular Drugs and Therapy 10/2012; · 2.67 Impact Factor
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    ABSTRACT: Cardiovascular remodeling found in later phases of two-kidney, one-clip (2K1C) hypertension may involve key mechanisms particularly including MMP-2, oxidative stress, transforming growth factor-β (TGF-β), and inactivation of the endogenous MMP inhibitor, the tissue inhibitor of MMP (TIMP)-4. We examined whether temporal cardiac remodeling resulting from 2K1C hypertension occurs concomitantly with alterations in cardiac collagen, MMP activity, MMP-2, TIMP-4, TGF-β, and reactive oxygen species (ROS) levels during the development of 2K1C hypertension. Sham-operated and 2K1C hypertensive rats were studied after 15, 30, and 75days of hypertension. Systolic blood pressure was monitored weekly. Left ventricle (LV) morphometry and fibrosis were evaluated in hematoxylin/eosin and picrosirius red-stained sections, respectively. Cardiac MMP-2 levels/activity was determined by gelatin zymography, immunofluorescence, and in situ zymography. TIMP-4 levels were determined by western blotting. Cardiac TGF-β levels were evaluated by immunofluorescence and ROS levels were evaluated with a dihydroethidium probe. 2K1C hypertension induced LV hypertrophy associated with augmented gelatinolytic activity at an early phase of hypertension and further increased after 75days of hypertension. These alterations were associated with increased cardiac MMP-2, TGF-β, and ROS in hypertensive rats. Higher TIMP-4 levels were found in hypertensive rats only after 75days after surgery. Our findings show that increased MMP-2 activity is associated with concomitant development of LV hypertrophy and increased TGF-β and ROS levels.
    Experimental and Molecular Pathology 10/2012; · 2.13 Impact Factor
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    ABSTRACT: With the introduction of fluoride as the main anticaries agent used in preventive dentistry, and perhaps an increase in fluoride in our food chain, dental fluorosis has become an increasing world-wide problem. Visible signs of fluorosis begin to become obvious on the enamel surface as opacities, implying some porosity in the tissue. The mechanisms that conduct the formation of fluorotic enamel are unknown, but should involve modifications in the basic physical-chemistry reactions of demineralization and remineralisation of the enamel of the teeth, which is the same reaction of formation of the enamel's hydroxyapatite (HAp) in the maturation phase. The increase of the amount of fluoride inside of the apatite will result in gradual increase of the lattice parameters. The aim of this work is to characterize the healthy and fluorotic enamel in human tooth using Synchrotron X-ray diffraction. All the scattering profile measurements were carried out at the X-ray diffraction beamline (XRD1) at the Brazilian Synchrotron Light Laboratory—LNLS, Campinas, Brazil. X-ray diffraction experiments were performed both in powder samples and polished surfaces. The powder samples were analyzed to obtain the characterization of a typical healthy enamel pattern. The polished surfaces were analyzed in specific areas that have been identified as fluorotic ones. X-ray diffraction data were obtained for all samples and these data were compared with the control samples and also with the literature data.
    Radiation Physics and Chemistry 10/2012; 81(10):1578–1585. · 1.38 Impact Factor
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    ABSTRACT: Growing evidence supports the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP-2 may affect the vascular tone and impair β-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant human MMP-2 (rhMMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during β(1) -adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP-2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 μg/kg/min. i.v. (or saline) over 180 min. in lambs that had received the same rhMMP-2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP-2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rhMMP-2 infusion. Moreover, dobutamine increased the cardiac index and left ventricular dP/dt(max) , and these effects were attenuated by rhMMP-2. The previous administration of doxycycline blunted rhMMP-2-induced changes in dobutamine responses. While the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rhMMP-2 exerts no major haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of β-adrenoreceptors.
    Basic & Clinical Pharmacology & Toxicology 08/2012; · 2.18 Impact Factor
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    ABSTRACT: Previously, we identified that the ATC/TTC haplotype formed by polymorphisms in the Interleukin-(IL)8 gene conferred susceptibility to chronic periodontitis (CP). The aim of the study was to investigate whether the IL8 haplotype ATC/TTC was associated with the volume of gingival crevicular fluid (GCF), the concentration of interleukin IL-8 in the GCF, as well as periodontal conditions in patients with CP in comparison to controls without CP. Seventy-nine individuals (CP: n=41, controls: n=38) were grouped according to the presence (susceptible for CP) or absence (not susceptible for CP) of the IL8 ATC/TTC haplotype. After periodontal clinical evaluation, they were subdivided by the presence or absence of CP. GCF was collected from each patient and the IL-8 levels were determined by ELISA. The GCF volume of each subject was measured by means of a calibrated electronic device. Comparisons of means between carriers and non-carriers of the ATC/TTC haplotype were evaluated using the Mann-Whitney test. Linear regression and stepwise linear regression analysis were used to analyse the association of the GCF volume with potential covariates and their contribution for the phenotype. We did not find significant differences of both periodontal conditions and IL-8 concentration in the GCF of patients with the presence or absence of the IL8 ATC/TTC haplotype. However, the GCF volume was significantly higher amongst the patients affected by CP that are absent for the IL8 ATC/TTC haplotype. In addition, linear regression analysis showed a statistically significant association between GCF volume and CP, IL8 haplotype ATC/TTC and IL-8 concentration. The IL8 haplotype of susceptibility to CP was neither associated with IL-8 cytokine levels nor with clinical periodontal parameters. Also, CP, IL8 haplotype and IL-8 concentration showed a positive association with the GCF volume levels in the studied patients.
    Archives of oral biology 08/2012; 57(10):1355-61. · 1.65 Impact Factor
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    ABSTRACT: Few studies have focused on the impact of hypertension on the progression of periodontitis (PD). The purpose of this study was to evaluate whether hypertension affects PD by enhancing bone loss even after the stimulus for PD induction is removed. Ligature-induced PD was created on the first mandibular molars of spontaneously hypertensive rats (SHR) and normotensive rats (Wistar Kyoto-WKY). The animals were assigned to non-ligated controls (C) and PD groups: WKY-C, WKY-PD, SHR-C, and SHR-PD. After 10 days, five animals of each group were killed and the ligatures of the other animals were removed. On the 21st day (11 days without PD induced), the remaining animals were killed. The jaws were defleshed and the amount of bone loss was measured. After 10 days, the PD groups showed more bone loss than its controls (P < .05); SHR-PD = 0.72 ± 0.05 mm, SHR-C = 0.39 ± 0.04 mm, WKY-PD = 0.75 ± 0.04 mm, and WKY-C = 0.56 ± 0.04 mm. The cumulative bone loss on day 21 (0.94 ± 0.13 mm) was significantly worse than on day 10 only in SHR-PD group (P < .05). The final bone loss differences between PD and C groups accounted for 102% (SHR) and 26% (WKY) increase in comparison with the initial control levels. Hypertension is associated with progressive alveolar bone loss even when the stimulus for PD induction is removed and it may be speculated that host condition perpetuates alveolar bone loss.
    Clinical and Experimental Hypertension 05/2012; · 1.28 Impact Factor
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    ABSTRACT: Increased reactive oxygen species (ROS) promote matrix metalloproteinase (MMP) activities and may underlie cardiomyocyte injury and the degradation of cardiac troponin I (cTI) during acute pulmonary thromboembolism (APT). We examined whether pretreatment or therapy with tempol (a ROS scavenger) prevents MMP activation and cardiomyocyte injury of APT. Anesthetized sheep received tempol infusion (1.0 mg kg(-1) min(-1), i.v.) or saline starting 30 min before or 30 min after APT (autologous blood clots). Control animals received saline. Hemodynamic measurements were performed. MMPs were studied in the right ventricle (RV) by gelatin zymography, fluorimetric activity assay, and in situ zymography. The ROS levels were determined in the RV and cTI were measured in serum samples. APT increased the pulmonary arterial pressure and pulmonary vascular resistance by 146 and 164%, respectively. Pretreatment or therapy with tempol attenuated these increases. While APT increased RV + dP/dt (max), tempol infusions had no effects. APT increased RV MMP-9 (but not MMP-2) levels. In line with these findings, APT increased RV MMP activities, and this finding was confirmed by in situ zymography. APT increased the RV ROS levels and tempol infusion, before or after APT, and blunted APT-induced increases in MMP-9 levels, MMP activities, in situ MMP activities, and ROS levels in the RV. cTI concentrations increased after APT, and tempol attenuated these increases. RV oxidative stress after APT increases the RV MMP activities, leading to the degradation of sarcomeric proteins, including cTI. Antioxidant treatment may prevent MMP activation and protect against cardiomyocyte injury after APT.
    Archiv für Experimentelle Pathologie und Pharmakologie 05/2012; 385(7):685-96. · 2.15 Impact Factor

Publication Stats

2k Citations
372.75 Total Impact Points


  • 2002–2014
    • University of São Paulo
      • • Faculdade de Medicina de Ribeirão Preto (FMRP)
      • • Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP)
      • • Faculdade de Odontologia de Ribeirão Preto (FORP)
      San Paulo, São Paulo, Brazil
  • 2000–2012
    • University of Campinas
      • • Faculdade de Ciências Médicas (FCM)
      • • Faculdade de Odontologia de Piracicaba (FOP)
      • • Departamento de Morfologia
      Campinas, Estado de Sao Paulo, Brazil
    • CEP America
      Emeryville, California, United States
  • 2011
    • University of Alberta
      • Department of Pharmacology
      Edmonton, Alberta, Canada
  • 2004–2011
    • Universidade de Ribeirão Preto
      Entre Rios, São Paulo, Brazil