Platelet hyperaggregability in high-fat fed rats: A role for intraplatelet reactive-oxygen species production

<p>Abstract</p> <p>Background</p> <p>Adiposity greatly increases the risk of atherothrombotic events, a pathological condition where a chronic state of oxidative stress is reported to play a major role. This study aimed to investigate the involvement of (NO)-soluble guanylyl cyclase (sGC) signaling pathway in the platelet dysfunction from high fat-fed (HFF) rats.</p> <p>Methods</p> <p>Male Wistar rats were fed for 10 weeks with standard chow (SCD) or high-fat diet (HFD). ADP (10 μM)- and thrombin (100 mU/ml)-induced washed platelet aggregation were evaluated. Measurement of intracellular levels of ROS levels was carried out using flow cytometry. Cyclic GMP levels were evaluated using ELISA kits.</p> <p>Results</p> <p>High-fat fed rats exhibited significant increases in body weight, epididymal fat, fasting glucose levels and glucose intolerance compared with SCD group. Platelet aggregation induced by ADP (<it>n </it>= 8) and thrombin from HFD rats (<it>n </it>= 8) were significantly greater (<it>P </it>< 0.05) compared with SCD group. Platelet activation with ADP increased by 54% the intraplatelet ROS production in HFD group, as measured by flow cytometry (<it>n </it>= 6). N-acetylcysteine (NAC; 1 mM) and PEG-catalase (1000 U/ml) fully prevented the increased ROS production and platelet hyperaggregability in HFD group. The NO donors sodium nitroprusside (SNP; 10 μM) and SNAP (10 μM), as well as the NO-independent soluble guanylyl cyclase stimulator BAY 41-2272 (10 μM) inhibited the platelet aggregation in HFD group with lower efficacy (<it>P </it>< 0.05) compared with SCD group. The cGMP levels in response to these agents were also markedly lower in HFD group (<it>P </it>< 0.05). The prostacyclin analogue iloprost (1 μM) reduced platelet aggregation in HFD and SCD rats in a similar fashion (<it>n </it>= 4).</p> <p>Conclusions</p> <p>Metabolic abnormalities as consequence of HFD cause platelet hyperaggregability involving enhanced intraplatelet ROS production and decreased NO bioavailability that appear to be accompanied by potential defects in the prosthetic haem group of soluble guanylyl cyclase.</p

Influence of acute pancreatitis on the in vitro responsiveness of rat mesenteric and pulmonary arteries

<p>Abstract</p> <p>Background</p> <p>Acute pancreatitis is an inflammatory disease characterized by local tissue injury and systemic inflammatory response leading to massive nitric oxide (NO) production and haemodynamic disturbances. Therefore, the aim of this work was to evaluate the vascular reactivity of pulmonary and mesenteric artery rings from rats submitted to experimental pancreatitis.</p> <p>Male Wistar rats were divided into three groups: saline (SAL); tauracholate (TAU) and phospholipase A₂(PLA₂). Pancreatitis was induced by administration of TAU or PLA₂from <it>Naja mocambique mocambique </it>into the common bile duct of rats, and after 4 h of duct injection the animals were sacrificed. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP) and phenylephrine (PHE) in isolated mesenteric and pulmonary arteries were obtained. Potency (pEC₅₀) and maximal responses (E_MAX) were determined. Blood samples were collected for biochemical analysis.</p> <p>Results</p> <p>In mesenteric rings, the potency for ACh was significantly decreased from animals treated with TAU (about 4.2-fold) or PLA₂(about 6.9-fold) compared to saline group without changes in the maximal responses. Neither pEC₅₀nor E_MAXvalues for Ach were altered in pulmonary rings in any group. Similarly, the pEC₅₀and the E_MAXvalues for SNP were not changed in both preparations in any group. The potency for PHE was significantly decreased in rat mesenteric and pulmonary rings from TAU group compared to SAL group (about 2.2- and 2.69-fold, for mesenteric and pulmonary rings, respectively). No changes were seen in the E_MAXfor PHE. The nitrite/nitrate (NO_x^-) levels were markedly increased in animals submitted to acute pancreatitis as compared to SAL group, approximately 76 and 68% in TAU and PLA₂protocol, respectively.</p> <p>Conclusion</p> <p>Acute pancreatitis provoked deleterious effects in endothelium-dependent relaxing response for ACh in mesenteric rings that were strongly associated with high plasma NO_x^-levels as consequence of intense inflammatory responses. Furthermore, the subsensitivity of contractile response to PHE in both mesenteric and pulmonary rings might be due to the complications of this pathological condition in the early stage of pancreatitis.</p

The Diabetic Vasculature: Physiological Mechanisms Of Dysfunction And Influence Of Aerobic Exercise Training In Animal Models.

Diabetes mellitus (DM) is associated with a number of complications of which chronic vascular complications are undoubtedly the most complex and significant consequence. With a significant impact on health care, 50-80% of people with diabetes die of cardiovascular disease (including coronary artery disease, stroke, peripheral vascular disease and other vascular disease), making it the major cause of morbidity and mortality in diabetic patients. A healthy lifestyle is essential in the management of DM, especially the inclusion of aerobic exercise, which has been shown effective in reducing the deleterious effects in vasculature. Interest in exercise studies has increased significantly with promising results that demonstrate a future for investigation. Considering the importance of this emerging field, the aim of this mini-review is to summarize and integrate animal studies investigating physiological mechanisms of vascular dysfunction and remodeling in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and how these are influenced by chronic aerobic exercise training.1021-

The diabetic vasculature: Physiological mechanisms of dysfunction and influence of aerobic exercise training in animal models

Diabetes mellitus (DM) is associated with a number of complications of which chronic vascular complications are undoubtedly the most complex and significant consequence. With a significant impact on health care, 50–80% of people with diabetes die of cardiovascular disease (including coronary artery disease, stroke, peripheral vascular disease and other vascular disease), making it the major cause of morbidity and mortality in diabetic patients. A healthy lifestyle is essential in the management of DM, especially the inclusion of aerobic exercise, which has been shown effective in reducing the deleterious effects in vasculature. Interest in exercise studies has increased significantly with promising results that demonstrate a future for investigation. Considering the importance of this emerging field, the aim of this mini-review is to summarize and integrate animal studies investigating physiological mechanisms of vascular dysfunction and remodeling in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and how these are influenced by chronic aerobic exercise training102119FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçã

Heart Rate Variability And Plasma Biomarkers In Patients With Type 1 Diabetes Mellitus: Effect Of A Bout Of Aerobic Exercise.

The aim of this study was to evaluate: (1) the cardiovascular parameters and plasma biomarkers in people with type 1 diabetes mellitus (T1DM) at baseline; and (2) the heart rate variability (HRV) and blood glucose in response to a session of aerobic exercise (AE) and during recovery period. Adults (18-35 years) were divided into two groups: control (CT, n=10) and T1DM (n=9). Anthropometric, cardiovascular, and biochemical parameters, and aerobic capacity (indirect peak oxygen uptake, VO2peak) were evaluated at baseline. Thirty minutes of AE (40-60% intensity) was performed on a treadmill. Blood glucose and HRV were determined at rest, during AE, and during the recovery period. Anthropometric measurements, cardiovascular parameters, aerobic capacity, and biochemical parameters were similar between the groups at baseline. In the T1DM group, blood glucose, glycated hemoglobin, and thiobarbituric acid reactive substances concentrations were increased while nitrite/nitrate (NOx(-)) levels were reduced. During AE, the magnitude of the reduction of blood glucose was greater than that during the recovery period in the T1DM group. The RR intervals and SDNN were reduced at rest as well as in the recovery period in T1DM subjects, whereas the RMSSD and pNN50 were only reduced during the recovery period. No changes were observed in low frequency (LF), high frequency (HF), and LF/HF ratio. Our study shows that T1DM patients on insulin therapy have poor blood glucose control with greater lipid peroxidation and lower NOx(-) levels, accompanied by an imbalance in autonomic function detected by the challenge of AE.11119-2

Aerobic exercise training prevents perivascular adipose tissue-induced endothelial dysfunction in thoracic aorta of obese mice

The mechanisms underlying the perivascular adipose tissue (PVAT) dysfunction in obesity are closely related to inflammation and oxidative stress. The present study aimed to investigate the effects of aerobic exercise training on PVAT-induced endothelial dysfunction of thoracic aorta of obese mice. Methods: Male mice C57BL6/JUnib (6-7 weeks) were divided into: sedentary (c-SD), trained (c-TR), obese sedentary (o-SD), and obese trained (o-TR). Obesity was induced by 16 weeks of high-fat diet and exercise training of moderate intensity started after 8 weeks of protocol and was performed on a treadmill, 5 days/week, for more 8 weeks, 60 min per session. The vascular responsiveness was performed in thoracic aorta in the absence (PVAT-) or in the presence (PVAT+) of PVAT. We analyzed circulatory parameters, protein expression, vascular nitric oxide (NO) production, and reactive oxygen species (ROS) in PVAT. Results: The maximal responses to acetylcholine (ACh) were reduced in PVAT+ compared with PVAT- rings in the o-SD group, accompanied by an increase in circulating glucose, insulin, resistin, leptin, and TNF-alpha. Additionally, the protein expression of iNOS and generation of ROS were increased in PVAT and production of vascular NO was reduced in the o-SD group compared with c-SD. In the o-TR group, the relaxation response to ACh was completely restored and the circulatory TNF-alpha, iNOS protein expression, and ROS were normalized with increased expression of Mn-SOD in PVAT, resulting in enhanced vascular NO production. Conclusion: The PVAT-induced endothelial dysfunction in thoracic aorta of obese mice, associated with circulatory inflammation and oxidative stress. Aerobic exercise training upregulated the anti-oxidant expression and decreased PVAT oxidative stress with beneficial impact on endothelium-dependent relaxation10FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/02960-1FAPESPFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/02960-1]; FAEPEX [0315/14

Differential coronary resistance microvessel remodeling between type 1 and type 2 diabetic mice: Impact of exercise training

The goals of the present study were to compare coronary resistance microvessel (CRM) remodeling between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mice, and to determine the impact of aerobic exercise training on CRM remodeling in diabetes. Eight week old male mice were divided into T1DM: control sedentary (Control-SD), T1DM sedentary (T1DM-SD) induced by streptozotocin, and T1DM exercise trained (T1DM-TR); T2DM: control sedentary (Db/db-SD), T2DM sedentary (db/db-SD), and T2DM trained (db/db-TR). Aerobic exercise training (TR) was performed on a mouse treadmill for 8 weeks. CRMs were isolated and mounted on a pressure myograph to measure and record vascular remodeling and mechanics. CRM diameters, wall thickness, stress-strain, incremental modulus remained unchanged in 11 DM-SD mice compared to control, and exercise training showed no effect. In contrast, CRMs isolated from db/db-SD mice exhibited decreased luminal diameter with thicker microvascular walls, which significantly increased the wall:lumen ratio (Db/db-SD: 5.8 +/- 0.3 vs. db/db-SD: 8.9 +/- 0.7, p<0.001). Compared to db/db-SD mice, coronary arterioles isolated from db/db-TR mice had similar internal diameter and wall thickness, while wall:lumen ratio (6.8 +/- 0.2, p<0.05) and growth index (db/db-SD: 16.2 vs. db/db-TR: 4.3, % over Db/db) were reduced. These data show that CRMs undergo adverse inward hypertrophic remodeling only in T2DM, but not T1DM, and that aerobic exercise training can partially mitigate this process. (C) 2012 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP