Sarcoplasmic reticulum calcium ATPase (SERCA) proteolysis by matrix metalloproteinase-2 contributes to vascular dysfunction in early hypertension.

AIMS: Hypertension is associated with an increased activity of matrix metalloproteinase (MMP)-2 in the vasculature, which, in turn, proteolyzes extra- and intracellular proteins that lead to vascular dysfunction. The activity of sarcoplasmic reticulum calcium ATPase (SERCA) is decreased in the aortas of hypertensive rats. Increased activity of MMP-2 proteolyzed SERCA in rat heart during ischemia and reperfusion injury, thus impairing cardiac function. Therefore, we examined whether increased activity of MMP-2 in early hypertension contributes to proteolyze SERCA in the aortas, thus leading to maladaptive vascular remodeling and dysfunction. MAIN METHODS: Male Sprague-Dawley rats were submitted to two kidney-one clip (2K-1C) or Sham surgery and treated with doxycycline. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. After 7 days, aortas were collected for zymography assays, Western blot to SERCA, ATPase activity assay, vascular reactivity, Ki-67 immunofluorescence and hematoxylin/eosin stain. KEY FINDINGS: SBP was increased in 2K-1C rats and doxycycline did not reduce it, but decreased MMP-2 activity and prevented SERCA proteolysis in aortas. Cross sectional area, media to lumen ratio and Ki-67 were all increased in the aortas of hypertensive rats and doxycycline decreased Ki-67. In 2K-1C rats, arterial relaxation to acetylcholine was impaired and doxycycline ameliorated it. SIGNIFICANCE: doxycycline reduced MMP-2 activity in aortas of 2K-1C rats and prevented proteolysis of SERCA and its dysfunction, thus ameliorating hypertension-induced vascular dysfunction.

Renal ischemia-reperfusion leads to hypertension and changes in proximal tubule Na+ transport and renin-angiotensin-aldosterone system: Role of NADPH oxidase.

Acute renal injury (AKI) is a risk factor for the development of hypertension, which involves oxidative stress, changes in Na+ handling, and the intrarenal renin-angiotensin-aldosterone system (RAAS) as underlying mechanisms. We investigated in rats whether renal ischemia-reperfusion (IR) leads to changes in the proximal tubule ATP-dependent Na+ transport and the intrarenal content of RAAS components, as well as the role of NADPH oxidase. Rats weighing 300-350 g were submitted to AKI by bilateral IR (n = 25). After IR injury, the animals were followed up for 4 weeks. One part (n = 7) received daily treatment with the NADPH oxidase inhibitor apocynin (100 mg/kg, drinking water), while another part (n = 9) received apocynin 24 h before and after IR. One group was submitted to sham surgery (n = 8). Four weeks after IR, the rats presented elevated systolic blood pressure, as well as increased lipid peroxidation, NADPH oxidase activity, (Na++K+)ATPase activity, and upregulation of type 1 angiotensin II receptor in the renal cortex. On the other hand, there was a decrease in Na+-ATPase activity and downregulation of the isoforms 1 and 2 of the angiotensin-converting enzyme, type 2 angiotensin II receptor, and of the α and ε isoforms of protein kinase C. Most of these alterations was prevented by both apocynin treatment protocols. Thus, we conclude that AKI-induced by IR may induce changes in proximal tubule ATPases and RAAS components compatible with renal Na+ retention and hypertension. These data also indicate that the NADPH oxidase represents a key factor in the origin of these alterations.

Pregnancy decreases O-GlcNAc-modified proteins in systemic arteries of normotensive and spontaneously hypertensive rats.

AIM: We determined the role played by O-linked N-acetylglucosamine (O-GlcNAc) of proteins in systemic arteries during late pregnancy in normotensive and hypertensive rats. MAIN METHODS: O-GlcNAc levels and O-GlcNAc modification of endothelial nitric oxide synthase (eNOS) were determined in aorta (conductance vessel) and mesenteric arteries (resistance vessels) of non-pregnant (NP) and pregnant (P) Wistar rats and spontaneously hypertensive rats (SHR). Vascular O-GlcNAc-modified proteins, O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) expression, and OGA activity were analyzed. Concentration-response to phenylephrine (PE) curves were constructed for arteries with and without endothelium. Arteries were treated with vehicle or PugNAc (OGA inhibitor, 100 µmol/L) in the presence of L-NAME (NOS inhibitor, 100 µmol/L). KEY FINDINGS: The content of vascular O-GlcNAc-modified proteins was lower, OGT and OGA expression did not change, and OGA activity was higher in arteries of P-Wistar rats and P-SHR compared to arteries of NP-groups. Reactivity to PE increased in arteries of P-Wistar rats treated with PugNAc compared to vehicle. O-GlcNAcylation of eNOS decreased in P-SHR compared to NP-SHR. PugNAc partially inhibited the effects of endothelium removal and L-NAME on reactivity to PE in arteries of P-Wistar rats. However, PugNAc did not alter reactivity to PE in arteries of P-SHR. Our data showed that pregnancy decreased the content of vascular O-GlcNAc-modified proteins. SIGNIFICANCE: Increased OGA activity and decreased O-GlcNAc modification of eNOS boosts eNOS activity in arteries of P-Wistar rats. In P-SHR, altered OGA activity may lower the content of O-GlcNAc-modified proteins, but decreased OGT activity seems a potential mechanism to reduce glycosylation.

Cadmium exposure activates NADPH oxidase, renin-angiotensin system and cyclooxygenase 2 pathways in arteries, inducing hypertension and vascular damage.

Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin-angiotensin system and COX2 pathway activation.

Blood pressure-lowering effects of a Bowman-Birk inhibitor and its derived peptides in normotensive and hypertensive rats.

Bioactive plant peptides have received considerable interest as potential antihypertensive agents with potentially fewer side effects than antihypertensive drugs. Here, the blood pressure-lowering effects of the Bowman-Birk protease inhibitor, BTCI, and its derived peptides, PepChy and PepTry, were investigated using normotensive (Wistar-WR) and spontaneously hypertensive rats (SHR). BTCI inhibited the proteases trypsin and chymotrypsin, respectively, at 6 µM and 40 µM, a 10-fold greater inhibition than observed with PepTry (60 µM) and PepChy (400 µM). These molecules also inhibited angiotensin converting enzyme (ACE) with IC50 values of 54.6 ± 2.9; 24.7 ± 1.1; and 24.4 ± 1.1 µM, respectively, occluding its catalytic site, as indicated by molecular docking simulation, mainly for PepChy and PepTry. Gavage administration of BTCI and the peptides promoted a decrease of systolic and diastolic blood pressure and an increase of renal and aortic vascular conductance. These effects were more expressive in SHR than in WR. Additionally, BTCI, PepChy and PepTry promoted coronary vasodilation and negative inotropic effects in isolated perfused hearts. The nitric oxide synthase inhibitor blunted the BTCI and PepChy, with no cardiac effects on PepTry. The findings of this study indicate a therapeutic potential of BTCI and its related peptides in the treatment of hypertension.

Exercise with blood flow restriction as a new tool for health improvement in hypertensive elderly women: the role of purinergic enzymes.

BACKGROUND: Purinergic signaling has been considered one of the mechanisms by which exercise exerts its antihypertensive effects; and research on the effects of blow flow restriction (BFR) exercise has increased as an alternative for elderly hypertensive patients. We analyzed the acute responses of NTPDase and adenosine deaminase (ADA) activities to low intensity aerobic exercise (LIAE) with BFR in lymphocytes of hypertensive elderly women. METHODS: Sixteen hypertensive elderly women performed three exercise protocols: LIAE; high intensity aerobic exercise (HIAE) and LIAE+BFR. Blood pressure, heart rate and blood collection were carried out before exercise, immediately after exercise and 30 min after exercise. NTPDase and ADA activities were measured in lymphocytes. RESULTS: Our results showed that LIAE+BFR triggered the same stimuli when compared to HIAE exercise regarding to NTPDases activities, suggesting that both protocols trigger an augment of these enzyme activities in response to: 1) increase in ATP release during exercise; and 2) need of adenosine generation to promotes anti-inflammatory responses in the recovery period. HIAE protocol was more effective than the others to trigger combined hypotensive and anti-inflammatory effects in the recovery period. CONCLUSIONS: This study showed that BFR is a good tool to promote anti-inflammatory effects similar (not equal) to HIAE. Moreover, LIAE+BFR promotes much more stimuli and adaptations related to immune functions than low intensity protocols, bringing more benefits for the hypertensive elderly population.

The Effect of Coronavirus Disease 2019 on Cardiovascular Diseases. / O Efeito da Doença de Coronavírus 2019 nas Doenças Cardiovasculares.

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting the world, seen in more than 1,300,000 patients. COVID-19 acts through the angiotensin-converting enzyme 2 (ACE2) receptor. Cardiovascular comorbidities are more common with COVID-19, and nearly 10% of cases develop myocarditis (22% of critical patients). Further research is needed to continue or discontinue ACE inhibitors and angiotensin receptor blockers, which are essential in hypertension and heart failure in COVID-19. Intensive research is promising for the treatment and prevention of COVID-19.

A doença de coronavírus 2019 (COVID-19) é uma pandemia global afetando o mundo, estando presente em mais de 1.300.000 pacientes. O COVID-19 age pelo receptor da enzima conversora de angiotensina 2 (ECA2). As comorbidades cardiovasculares são mais frequentes com COVID-19, e cerca 10% de casos desenvolvem miocardite (22% de pacientes críticas). Mais pesquisas serão necessárias para continuar ou descontinuar inibidores de ECA e bloqueadores dos receptores da angiotensina, que são essenciais para hipertensão e insuficiência cardíaca em COVID-19. Pesquisa intensiva é promissora para o tratamento e a prevenção da COVID-19.

Electrical stimulation of the carotid sinus lowers arterial pressure and improves heart rate variability in L-NAME hypertensive conscious rats.

We evaluated the effects of long-term (48 h) electrical stimulation of the carotid sinus (CS) in hypertensive rats. L-NAME-treated (10 days) Wistar rats were implanted with a catheter in the femoral artery and a miniaturized electrical stimulator attached to electrodes positioned around the left CS, encompassing the CS nerve. One day after implantation, arterial pressure (AP) was directly recorded in conscious animals for 60 min. Square pulses (1 ms, 3 V, 30 Hz) were applied intermittently (20/20 s ON/OFF) to the CS for 48 h. After the end of stimulation, AP was recorded again. Nonstimulated rats (control group) and rats without electrodes around the CS (sham-operated) were also studied. Next, the animals were decapitated, and segments of mesenteric resistance arteries were removed to study vascular function. After the stimulation period, AP was 16 ± 5 mmHg lower in the stimulated group, whereas sham-operated and control rats showed similar AP between the first and second recording periods. Heart rate variability (HRV) evaluated using time and frequency domain tools and a nonlinear approach (symbolic analysis) suggested that hypertensive rats with electrodes around the CS, stimulated or not, exhibited a shift in cardiac sympathovagal balance towards parasympathetic tone. The relaxation response to acetylcholine in endothelium-intact mesenteric arteries was enhanced in rats that underwent CS stimulation for 48 h. In conclusion, long-term CS stimulation is effective in reducing AP levels, improving HRV and increasing mesenteric vascular relaxation in L-NAME hypertensive rats. Moreover, only the presence of electrodes around the CS is effective in eliciting changes in HRV similar to those observed in stimulated rats.

O Efeito da Doença de Coronavírus 2019 nas Doenças Cardiovasculares / The Effect of Coronavirus Disease 2019 on Cardiovascular Diseases

Resumo A doença de coronavírus 2019 (COVID-19) é uma pandemia global afetando o mundo, estando presente em mais de 1.300.000 pacientes. O COVID-19 age pelo receptor da enzima conversora de angiotensina 2 (ECA2). As comorbidades cardiovasculares são mais frequentes com COVID-19, e cerca 10% de casos desenvolvem miocardite (22% de pacientes críticas). Mais pesquisas serão necessárias para continuar ou descontinuar inibidores de ECA e bloqueadores dos receptores da angiotensina, que são essenciais para hipertensão e insuficiência cardíaca em COVID-19. Pesquisa intensiva é promissora para o tratamento e a prevenção da COVID-19.

Abstract Coronavirus disease 2019 (COVID-19) is a global pandemic affecting the world, seen in more than 1,300,000 patients. COVID-19 acts through the angiotensin-converting enzyme 2 (ACE2) receptor. Cardiovascular comorbidities are more common with COVID-19, and nearly 10% of cases develop myocarditis (22% of critical patients). Further research is needed to continue or discontinue ACE inhibitors and angiotensin receptor blockers, which are essential in hypertension and heart failure in COVID-19. Intensive research is promising for the treatment and prevention of COVID-19.

Plasma levels of matrix metalloproteinase-9 are elevated in individuals with hypertensive crisis.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) participates in the degradation of components of the extracellular matrix and it is involved in vascular remodeling and vasomotor changes. The aim of this study was to investigate the plasma levels of MMP-9 in acute vascular alterations due to hypertensive crisis. METHODS: This cross-sectional study was performed in 40 normotensive (NT) and 58 controlled hypertensive subjects (CHyp) followed up in outpatient clinic. Moreover, 57 patients with hypertensive emergency (HypEmerg) and 43 in hypertensive urgency (HypUrg), seen in emergency department, were also included. Hypertensive crisis was divided into HypEmerg, which was characterized by levels of systolic blood pressure (BP) ≥ 180 mmHg and/or diastolic BP ≥ 120 mmHg complicated with target-organ damage (TOD), and HypUrg, defined by BP elevation without TOD. Univariate and multivariate regression analysis was performed to identify the influence of independent variables on MMP-9 levels. A p-value < 0.05 was considered statistically significant. RESULTS: The mean age was 43.5 years in the NT group (11 men); 57.7 years in the CHyp group (29 men); 59.4 years in the HypUrg group (21 men) and 62.4 years in the HypEmerg group (31 men). The age was statistically different in the NT group compared to other 3 groups. The mean BP was 116.5 ± 13.9/72.4 ± 10.6 mmHg for NT, 123.2 ± 12.6/79 ± 9.2 for CHyp, 194.1 ± 24.3/121.4 ± 17.3 for HypUrg and 191.6 ± 34.3/121.7 ± 18.8 mmHg for HypEmerg, respectively (p-value< 0.0001 between groups). MMP-9 levels were statistically different between the HypEmerg (2.31 ± 0.2 ng/mL) and HypUrg groups (2.17 ± 0.3 ng/mL) compared to the NT (1.94 ± 0.3 ng/mL) (p-value < 0.01 and p-value < 0.05, respectively) and CHyp groups (1.92 ± 0.2 ng/mL) (p-value < 0.01). Uric acid was the only independent variable for predicting MMP-9 levels (p-value = 0.001). CONCLUSION: MMP-9 concentrations are significantly higher in the hypertensive crisis groups (urgency and emergency) compared to the control groups. Therefore, MMP-9 may be a biomarker or mediator of pathophysiologic pathways in cases of acute elevations of blood pressure.

Sildenafil reduces aortic endothelial dysfunction and structural damage in spontaneously hypertensive rats: Role of NO, NADPH and COX-1 pathways.

Arterial hypertension is a condition associated with endothelial dysfunction, accompanied by an imbalance in the production of reactive oxygen species (ROS) and NO. The aim of this study was to investigate and elucidate the possible mechanisms of sildenafil, a selective phosphodiesterase-5 inhibitor, actions on endothelial function in aortas from spontaneously hypertensive rats (SHR). SHR treated with sildenafil (40 mg/kg/day, p.o., 3 weeks) were compared to untreated SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and vascular reactivity was determined in isolated rat aortic rings. Circulating endothelial progenitor cells and systemic ROS were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Scanning electron microscopy was used for structural analysis of the endothelial surface. Sildenafil reduced high SBP and partially restored the vasodilator response to acetylcholine and sodium nitroprusside in SHR aortic rings. Using selective inhibitors, our experiments revealed an augmented participation of NO, with a simultaneous decrease of oxidative stress and of cyclooxygenase-1 (COX-1)-derived prostanoids contribution in the endothelium-dependent vasodilation in sildenafil-treated SHR compared to non-treated SHR. Also, the relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR and sildenafil restored the pro-oxidant/antioxidant balance and the endothelial architecture. In conclusion, sildenafil reverses endothelial dysfunction in SHR by improving vascular relaxation to acetylcholine with increased NO bioavailability, reducing the oxidative stress and COX-1 prostanoids, and improving cGMP/PKG signaling. Also, sildenafil reduces structural endothelial damage. Thus, sildenafil is a promising novel pharmacologic strategy to treat endothelial dysfunction in hypertensive states reinforcing its potential role as adjuvant in the pharmacotherapy of cardiovascular diseases.

Chronic Treatment With Acetylcholinesterase Inhibitors Attenuates Vascular Dysfunction in Spontaneously Hypertensive Rats.

BACKGROUND: Acetylcholinesterase inhibition prevents autonomic imbalance, reduces inflammation, and attenuates the development of hypertension. Considering that vascular dysfunction is a crucial feature of arterial hypertension, we investigated the effects of chronic administration of acetylcholinesterase inhibitors-pyridostigmine or donepezil-on vascular reactivity of spontaneously hypertensive rats (SHR). METHODS: Endothelium-dependent relaxant responses to acetylcholine (ACh) and contractile responses induced by electric field stimulation (EFS) and alpha-adrenergic agonist were studied in mesenteric resistance arteries from SHR and Wistar Kyoto rats. SHR were treated for 16 weeks with vehicle, pyridostigmine (1.5 mg/kg/day) or donepezil (1.4 mg/kg/day). RESULTS: Pyridostigmine and donepezil decreased the vasoconstrictor responses to EFS, which were increased in vehicle-treated SHR. Acetylcholinesterase inhibition increased the modulatory effects of nitric oxide (NO) on SHR vascular reactivity, that is, N(ω)-nitro-(L)-arginine methyl ester (L-NAME) increased EFS-induced contractions and reduced ACh-induced relaxation, with more significant effects in pyridostigmine- and donepezil-treated SHR. The acetylcholinesterase inhibitors also decreased vascular reactive oxygen species levels. CONCLUSIONS: This study demonstrates for the first time that long-term administration of acetylcholinesterase inhibitors, pyridostigmine or donepezil, attenuates vascular reactivity dysfunction in SHR by decreasing reactive oxygen species generation and increasing NO bioavailability; possibly via increased endothelial NO synthase activity, and inhibition of NADPH oxidase activity.

CBS promoter hypermethylation increases the risk of hypertension and stroke.

OBJECTIVES: Cystathionine ß-synthase is a major enzyme in the metabolism of plasma homocysteine. Hyperhomocysteinemia is positively associated with hypertension and stroke. The present study was performed to examine the possible effects of Cystathionine ß-synthase promoter methylation on the development of hypertension and stroke. METHODS: Using quantitative methylation-specific PCR, we determined the Cystathionine ß-synthase methylation levels in 218 healthy individuals and 132 and 243 age- and gender-matched stroke and hypertensive patients, respectively. The relative changes in Cystathionine ß-synthase promoter methylation were analyzed using the 2-ΔΔCt method. The percent of the methylated reference of Cystathionine ß-synthase was used to represent the Cystathionine ß-synthase promoter methylation levels. RESULTS: In this study, the Cystathionine ß-synthase promoter methylation levels of hypertensive and stroke participants were both higher than that of the healthy individuals (median percentages of the methylated reference were 50.61%, 38.05% and 30.53%, respectively, all p<0.001). Multivariable analysis showed that Cystathionine ß-synthase promoter hypermethylation increased the risk of hypertension [odds ratio, OR (95% confidence interval, CI)=1.035 (1.025-1.045)] and stroke [OR (95% CI)=1.015 (1.003-1.028)]. The area under the curve of Cystathionine ß-synthase promoter methylation was 0.844 (95% CI: 0.796-0.892) in male patients with hypertension and 0.722 (95% CI: 0.653-0.799) in male patients with stroke. CONCLUSION: Cystathionine ß-synthase promoter hypermethylation increases the risk of hypertension and stroke, especially in male patients.

CBS promoter hypermethylation increases the risk of hypertension and stroke

OBJECTIVES: Cystathionine β-synthase is a major enzyme in the metabolism of plasma homocysteine. Hyperhomocysteinemia is positively associated with hypertension and stroke. The present study was performed to examine the possible effects of Cystathionine β-synthase promoter methylation on the development of hypertension and stroke. METHODS: Using quantitative methylation-specific PCR, we determined the Cystathionine β-synthase methylation levels in 218 healthy individuals and 132 and 243 age- and gender-matched stroke and hypertensive patients, respectively. The relative changes in Cystathionine β-synthase promoter methylation were analyzed using the 2-ΔΔCt method. The percent of the methylated reference of Cystathionine β-synthase was used to represent the Cystathionine β-synthase promoter methylation levels. RESULTS: In this study, the Cystathionine β-synthase promoter methylation levels of hypertensive and stroke participants were both higher than that of the healthy individuals (median percentages of the methylated reference were 50.61%, 38.05% and 30.53%, respectively, all p<0.001). Multivariable analysis showed that Cystathionine β-synthase promoter hypermethylation increased the risk of hypertension [odds ratio, OR (95% confidence interval, CI)=1.035 (1.025-1.045)] and stroke [OR (95% CI)=1.015 (1.003-1.028)]. The area under the curve of Cystathionine β-synthase promoter methylation was 0.844 (95% CI: 0.796-0.892) in male patients with hypertension and 0.722 (95% CI: 0.653-0.799) in male patients with stroke. CONCLUSION: Cystathionine β-synthase promoter hypermethylation increases the risk of hypertension and stroke, especially in male patients.

Xanthine oxidase activity in patients with age-related cataract associated with hypertension.

Reactive oxygen species and lipid peroxidation are important factors that contribute to the development of age-related cataract. The study included 130 patients with age-related cataract, 69 of whom were diagnosed with hypertension (HT), 20 with hypertension and type 2 diabetes mellitus (DM), and 41 had no accompanying condition. The following parameters were measured in the serum of the examinees: products of lipid peroxidation malondialdehyde (MDA) and lipofuscin-like fluorophores (LLF), activity of prooxidative enzymes xanthine oxidase (XO) and myeloperoxidase (MPO), antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the concentration of thiol groups, and the ferric reducing activity of plasma. The activity of prooxidative enzymes XO and MPO was higher in the plasma of patients with HT (XO=9.0±1.2 U/L; MPO=77.3±8.4 U/L) and with HT and DM (XO=11.9±0.9 U/L; MPO=89.5±5.0 U/L) compared to patients with age-related cataract (XO=6.2±0.9 U/L; MPO=52.4±6.3 U/L; P<0.01). Our research has shown that patients with age-related cataract and hypertension were exposed to increased oxidative damage of biomolecules, based on the increased plasma LLF and MDA content and decreased levels of thiol groups. Oxidative changes of biomolecules in these patients were associated with increased activity of the XO, MPO, and GPx enzymes and a lower extracellular SOD activity and total ferric reductive ability of plasma.

Xanthine oxidase activity in patients with age-related cataract associated with hypertension

Reactive oxygen species and lipid peroxidation are important factors that contribute to the development of age-related cataract. The study included 130 patients with age-related cataract, 69 of whom were diagnosed with hypertension (HT), 20 with hypertension and type 2 diabetes mellitus (DM), and 41 had no accompanying condition. The following parameters were measured in the serum of the examinees: products of lipid peroxidation malondialdehyde (MDA) and lipofuscin-like fluorophores (LLF), activity of prooxidative enzymes xanthine oxidase (XO) and myeloperoxidase (MPO), antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the concentration of thiol groups, and the ferric reducing activity of plasma. The activity of prooxidative enzymes XO and MPO was higher in the plasma of patients with HT (XO=9.0±1.2 U/L; MPO=77.3±8.4 U/L) and with HT and DM (XO=11.9±0.9 U/L; MPO=89.5±5.0 U/L) compared to patients with age-related cataract (XO=6.2±0.9 U/L; MPO=52.4±6.3 U/L; P<0.01). Our research has shown that patients with age-related cataract and hypertension were exposed to increased oxidative damage of biomolecules, based on the increased plasma LLF and MDA content and decreased levels of thiol groups. Oxidative changes of biomolecules in these patients were associated with increased activity of the XO, MPO, and GPx enzymes and a lower extracellular SOD activity and total ferric reductive ability of plasma.

Aluminum exposure at human dietary levels promotes vascular dysfunction and increases blood pressure in rats: A concerted action of NAD(P)H oxidase and COX-2.

Aluminum (Al) is a non-essential metal and a significant environmental contaminant and is associated with a number of human diseases including cardiovascular disease. We investigated the effects of Al exposure at doses similar to human dietary levels on the cardiovascular system over a 60day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60days as follows: a) Untreated - ultrapure water; b) AlCl3 at a dose of 8.3mg/kg bw for 60days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42days as follows: C) Untreated - ultrapure water; d) AlCl3 at 100mg/kg bw for 42days, representing a high level of human exposure to Al. Effects on systolic blood pressure (SBP) and vascular function of aortic and mesenteric resistance arteries (MRA) were studied. Endothelium and smooth muscle integrity were evaluated by concentration-response curves to acetylcholine (ACh) and sodium nitroprusside. Vasoconstrictor responses to phenylephrine (Phe) in the presence and absence of endothelium and in the presence of the NOS inhibitor L-NAME, the potassium channels blocker TEA, the NAD(P)H oxidase inhibitor apocynin, superoxide dismutase (SOD), the non-selective COX inhibitor indomethacin and the selective COX-2 inhibitor NS 398 were analyzed. Vascular reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity, were measured. The mRNA expressions of eNOS, NAD(P)H oxidase 1 and 2, SOD1, COX-2 and thromboxane A2 receptor (TXA-2 R) were also investigated. Al exposure at human dietary levels impaired the cardiovascular system and these effects were almost the same as Al exposure at much higher levels. Al increased SBP, decreased ACh-induced relaxation, increased response to Phe, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide (NO), the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric arteries. Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Our results point to an excess of ROS mainly from NAD(P)H oxidase after Al exposure and the increased vascular prostanoids from COX-2 acting in concert to decrease NO bioavailability, thus inducing vascular dysfunction and increasing blood pressure. Therefore, 60-day chronic exposure to Al, which reflects common human dietary Al intake, appears to pose a risk for the cardiovascular system.

90-kDa N-domain angiotensin I-converting enzyme (ACE): possible marker for hypertension in a renal transplant model.

INTRODUCTION: Hypertension is nearly universal in kidney transplant and several factors are associated with post transplant hypertension, including immunosuppressive medications and genetic predisposition. OBJECTIVE: The aims were to evaluate the effects of spontaneously hypertensive rats (SHR) kidney transplantation in Wistar rats and the possible transference of 80/90-kDa N-domain ACE. METHODS: To do so, the data from Wistar recipients of kidney from SHR were compared to data from transplanted Wistar submitted to CsA treatment and, to Wistar Sham. RESULTS AND DISCUSSION: Despite the unaltered blood pressure observed at early stages, 80/90-kDa ACE was found expressed in the urine of rats 7 and 15 days after transplantation, which was intense when rats became hypertensive 30 days post-surgery. CONCLUSION: Our data show that this enzyme is associated with the development of hypertension, and this marker appears in the urine before any substantial blood pressure alteration.

90-kDa N-domain angiotensin I-converting enzyme (ACE): possible marker for hypertension in a renal transplant model / Enzima conversora de angiotensina I (ECA) N-domínio 90-kDa: possível marcador para hipertensão em modelo de transplante renal

Abstract Introduction: Hypertension is nearly universal in kidney transplant and several factors are associated with post transplant hypertension, including immunosuppressive medications and genetic predisposition. Objective: The aims were to evaluate the effects of spontaneously hypertensive rats (SHR) kidney transplantation in Wistar rats and the possible transference of 80/90-kDa N-domain ACE. Methods: To do so, the data from Wistar recipients of kidney from SHR were compared to data from transplanted Wistar submitted to CsA treatment and, to Wistar Sham. Results and Discussion: Despite the unaltered blood pressure observed at early stages, 80/90-kDa ACE was found expressed in the urine of rats 7 and 15 days after transplantation, which was intense when rats became hypertensive 30 days post-surgery. Conclusion: Our data show that this enzyme is associated with the development of hypertension, and this marker appears in the urine before any substantial blood pressure alteration.

Resumo Introdução: A hipertensão é altamente prevalente pós-transplante renal e vários fatores estão associados incluindo o tratamento com imunossupressores e a predisposição genética. Objetivo: Os objetivos foram avaliar os efeitos do transplante do rim de ratos espontaneamente hipertensos (SHR) em ratos Wistar, e a possível transferência da ECA N-domínio de 80/90-kDa para os tecidos dos receptores. Métodos: Para isso, os dados dos animais Wistar receptores dos rins de SHR foram comparados aos dados dos Wistar submetidos ao tratamento com CsA e Wistar Sham. Resultados e Discussão: Apesar da pressão arterial permanecer inalterada nos estágios iniciais pós-transplante renal, a expressão da ECA de 80/90-kDa foi identificada na urina de ratos 7 e 15 dias após o transplante, e de forma mais intensa aos 30 dias após a cirurgia, quando os animais tornaram-se hipertensos. Conclusão: Nossos dados mostram que ECA N-domínio está associada ao desenvolvimento da hipertensão, e que este marcador pode ser identificado na urina pós-transplante renal antes mesmo de qualquer alteração da pressão arterial.

Increased Circulating Tissue Inhibitor of Metalloproteinase-2 Is Associated With Resistant Hypertension.

Resistant hypertension (RH) is associated with organ damage and cardiovascular risk. Evidence suggests the involvement of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in hypertension and in cardiovascular remodeling. The aim of this study was to assess the levels of MMP-2 and TIMP-2 in RH and its relation with organ damage, including arterial stiffness and cardiac hypertrophy. MMP-2 and TIMP-2 levels were compared among 19 patients with normotension (NT), 116 with nonresistant hypertension (HTN) and 116 patients with resistant HTN (RH). MMP-2 levels showed no differences among NT, HTN, and RH groups, while TIMP-2 levels were higher in RH compared with HTN and NT groups (90.0 [76.1-107.3] vs 70.1 [57.7-88.3] vs 54.7 [40.9-58.1] ng/mL, P<.01), respectively. MMP-2/TIMP-2 ratio was reduced in the RH group compared with the HTN and NT groups (2.7 [1.9-3.4] vs 3.3 [2.6-4.2] vs 4.9 [4.5-5.3], P<.01), respectively. No associations were found between MMP-2 levels, TIMP-2, and MMP-2/TIMP-2 ratio with cardiac hypertrophy and arterial stiffness in the RH and HTN groups. Finally, in a regression analysis, reduced MMP-2/TIMP-2 ratio and increased TIMP-2 levels were independently associated with RH. The present findings provide evidence that TIMP-2 is associated with RH and might be a possible biomarker for screening RH patients.