Debora C. Souza-Costa

The effect of sildenafil on pulmonary embolism-induced oxidative stress and pulmonary hypertension.

Acute pulmonary embolism (APE) is a major cause of pulmonary hypertension and death. We examined the effects of sildenafil on the hemodynamic changes caused by APE in anesthetized dogs. Sham-operated dogs (n = 3) received only saline. APE was induced by stepwise IV injections of 300 &mgr;m microspheres in amounts adjusted to increase mean pulmonary artery pressures by 20 mm Hg. Hemodynamic evaluation was performed at baseline, after APE was induced, and then after sildenafil 0.25 mg/kg (n = 8), or sildenafil 1 mg/kg + 0.3 mg · kg−1 · h−1 (n = 8) or saline (n = 9) infusions were started. Similar experiments were conducted to examine the effects of sildenafil in rat isolated perfused lung preparation. Plasma thiobarbituric acid reactive species were also determined in both studies to measure oxidative stress. Both doses of sildenafil reduced mean pulmonary artery pressures in dogs by approximately 8 to 16 mm Hg (both P < 0.05) and attenuated the increase in oxidative stress after APE. Mean arterial blood pressure remained unaltered after both doses of sildenafil. Sildenafil produced similar effects after APE in rat isolated perfused lung preparation. These findings indicate that IV sildenafil can selectively attenuate the increases in mean pulmonary artery pressures after APE, possibly through antioxidant mechanisms.

Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9.

Objective: Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of acute pulmonary embolism (APE)‐induced pulmonary hypertension. Here, we evaluate the effects of atorvastatin pretreatment on APE‐induced pulmonary hypertension, 24‐hr mortality rate, and changes in plasma and lung MMP‐2 and MMP‐9 activities. Design: Controlled animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Interventions: Rats received atorvastatin (30 mg/kg/day orally) or tap water for 2 wks. In study 1, we examined whether atorvastatin affected APE‐induced pulmonary hypertension by using a rat isolated lung perfusion model of APE. In study 2, we examined whether atorvastatin affects the survival rate after APE, which was induced by rapid intravenous injection of 14 mg/kg of a suspension of microspheres (or saline) into the tail vein. Measurements and Main Results: Plasma nitrite/nitrate concentrations were measured by chemiluminescence. Pretreatment with atorvastatin was associated with 49% higher nitrite/nitrate levels compared with controls (p < .05). In study 1, whereas APE increased mean pulmonary artery pressure (MPAP) by 13.0 ± 1.6 mm Hg in perfused lungs isolated from rats pretreated with water, pretreatment with atorvastatin attenuated by 27% the increases in MPAP after APE. In study 2, pretreatment with atorvastatin was associated with a significant increase in 24‐hr survival rate after APE, which was 48% in embolized rats pretreated with water and 64% in rats pretreated with atorvastatin (p < .05). Gelatin zymography of lung and plasma MMP‐2 and MMP‐9 was performed. Lungs and plasma from embolized rats showed higher levels of both pro‐ and activated forms of MMP‐9 compared with those from nonembolized animals (all p < .05). However, pretreatment with atorvastatin attenuated by 32% the increases in lung‐activated MMP‐9 levels after APE (p < .05). Conclusions: These results suggest that pretreatment with atorvastatin attenuates APE‐induced pulmonary hypertension and increases 24‐hr survival rate by mechanisms that result in attenuated increases in lung activated MMP‐9 after APE.

Assessment of matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in obese children and adolescents

OBJECTIVES To compare the circulating levels of matrix metalloproteinase (MMP)-8, pro-MMP-2, pro-MMP-9, and total MMP-9, their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2, and the MMP-8/TIMP-1, MMP-9/TIMP-1, and MMP-2/TIMP-2 ratios in normotensive obese children and adolescents with those found in non obese children and adolescents. DESIGN AND METHODS We studied 40 obese and 40 non obese (controls) children and adolescents in this cross-sectional study. MMP and TIMP concentrations were measured in plasma samples by gelatin zymography and ELISA. RESULTS Obese children and adolescents had higher circulating MMP-8 concentrations, lower plasma TIMP-1 concentrations, and higher MMP-8/TIMP-1 ratios than non obese controls (P<0.05). We found no differences in pro-MMP-9 or total MMP-9 levels, or in MMP-9/TIMP-1 ratios between groups (P>0.05). While we found no significant differences in pro-MMP-2 levels (P>0.05) obese subjects had higher TIMP-2 concentrations and lower pro-MMP-2/TIMP-2 ratios (P<0.05) than non obese controls. CONCLUSIONS In conclusion, we found evidence indicating higher net MMP-8 (but not MMP-9 and MMP-2) activity in childhood obesity. The increased MMP-8 levels found in obese children suggest a possibly relevant pathophysiological mechanism that may be involved in the increase of cardiovascular risk associated with childhood obesity.

Identification of periodontal pathogens and severity of periodontitis in patients with and without chronic kidney disease

OBJECTIVE In this study of patients with chronic periodontitis (CP), the severity of the disease and the main periodontal pathogens identified in patients with chronic kidney disease (CKD) were compared with those detected in individuals without systemic disease. DESIGN Nineteen patients with CP without evidence of systemic disease (control group), 25 patients with CP and CKD who were in the pre-dialysis stages (pre-dialysis group), and 22 patients with CP and CKD who were on renal replacement therapy (RRT group) were examined. The severity of CP was based on the investigation of probing depth (PD) and clinical attachment level (CAL). The definition and stage of CKD were based on the criteria proposed by the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation. Glomerular filtration rate (GFR) was estimated using the equation of Modification of Diet in Renal Disease and the identification of microorganisms in subgingival plaque was performed using polymerase chain reaction (PCR). RESULTS Candida albicans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola were more common in patients who were on RRT and pre-dialysis than in control subjects. CP was more severe in patients with CKD. A strong association was observed between the frequency of C. albicans (P = 0.056), P.gingivalis (P = 0.008), T. denticola (P = 0.013) and CAL, when CKD patients were compared with the control group. CONCLUSION CP is more severe and is associated with increased frequency of C. albicans, P. gingivalis, T. forsythia, and T. denticola in patients with CKD.

Vascular Endothelial Growth Factor Haplotypes Associated with Childhood Obesity

Expansion of adipose tissue in obesity is associated with angiogenesis and adipose tissue mass depends on neovascularization. Vascular endothelial growth factor (VEGF) is the main angiogenic factor in the adipose tissue, and VEGF expression is tightly regulated at both transcriptional and translational levels. However, no previous study has tested the hypothesis that genetic polymorphisms in the VEGF gene could affect susceptibility to obesity. To test this hypothesis, we compared the distribution of genotypes and haplotypes including three VEGF genetic polymorphisms in obese children and adolescents with those found in healthy controls. We studied 172 healthy children and adolescents and 113 obese children and adolescents. Genotypes of three clinically relevant VEGF polymorphisms in the promoter region (C-2578A, G-1154A, and G-634C) of the VEGF gene were determined by TaqMan allele discrimination assay and real-time polymerase chain reaction. VEGF haplotypes were inferred using Haplo.stats and PHASE 2.1 programs. We found no differences in the distributions of VEGF genotypes and alleles (p > 0.05). However, the CAG haplotype was more frequent in the obese group than in the control group (4% versus 0%, respectively, in white subjects; p = 0.008; odds ratio = 10.148 (95% confidence interval: 1.098-93.788). Our findings suggest that VEGF haplotypes affect susceptibility to obesity in children and adolescents.

Increased activity of MMP‐2 in hypertensive obese children is associated with hypoadiponectinemia

To compare the circulating levels of MMP‐2 and TIMP‐2 and the MMP‐2/TIMP‐2 ratio in control, obese, and obese hypertensive children and adolescents and to assess whether hypoadiponectinemia is associated with MMP‐2 and TIMP‐2 levels and MMP‐2/TIMP‐2 ratios.

Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity

OBJECTIVE Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. METHODS This was a case-control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. RESULTS As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. CONCLUSION The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.