Can Deep Water Exercise Training Improve Arterial Stiffness in Women with Metabolic Syndrome?

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Relationships between Peak Oxygen Uptake and Arterial Function: a Preliminary Study

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Perivascular Adipose Tissue Diminishes Nitric Oxide Bioavailability in Metabolic Syndrome

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Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration.

Pulmonary arterial hypertension (PAH) is a complex degenerative disorder marked by aberrant vascular remodeling associated with hyperproliferation and migration of endothelial cells (ECs). Previous reports implicated bone morphogenetic protein antagonist Gremlin 1 in this process; however, little is known of the molecular mechanisms involved. The current study was designed to test whether redox signaling initiated by NADPH oxidase 1 (Nox1) could promote transcription factor CREB activation by redox factor 1 (Ref-1), transactivation of Gremlin1 transcription, EC migration, and proliferation. Human pulmonary arterial EC (HPAECs) exposed in vitro to hypoxia to recapitulate PAH signaling displayed induced Nox1 expression, reactive oxygen species (ROS) production, PKA activity, CREB phosphorylation, and CREB:CRE motif binding. These responses were abrogated by selective Nox1 inhibitor NoxA1ds and/or siRNA Nox1. Nox1-activated CREB migrated to the nucleus and bound to Ref-1 leading to CREB:CRE binding and Gremlin1 transcription. CHiP assay and CREB gene-silencing illustrated that CREB is pivotal for hypoxia-induced Gremlin1, which, in turn, stimulates EC proliferation and migration. In vivo, participation of Nox1, CREB, and Gremlin1, as well as CREB:CRE binding was corroborated in a rat PAH model. Activation of a previously unidentified Nox1-PKA-CREB/Ref-1 signaling pathway in pulmonary endothelial cells leads to Gremlin1 transactivation, proliferation and migration. These findings reveal a new signaling pathway by which Nox1 via induction of CREB and Gremlin1 signaling contributes to vascular remodeling and provide preclinical indication of its significance in PAH

NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow.

First described as essential to the phagocytic activity of leukocytes, Nox2-derived ROS have emerged as mediators of a range of cellular and tissue responses across species from salubrious to deleterious consequences. Knowledge of their role in inflammation is limited, however. We postulated that TNFα-induced endothelial reactive oxygen species (ROS) generation and pro-inflammatory signaling would be ameliorated by targeting Nox2. Herein, we in silico-modelled two first-in-class Nox2 inhibitors developed in our laboratory, explored their cellular mechanism of action and tested their efficacy in in vitro and mouse in vivo models of inflammation. Our data show that these inhibitors (CPP11G and CPP11H) disrupted canonical Nox2 organizing factor, p47phox, translocation to Nox2 in the plasma membrane; and abolished ROS production, markedly attenuated stress-responsive MAPK signaling and downstream AP-1 and NFκB nuclear translocation in human cells. Consequently, cell adhesion molecule expression and monocyte adherence were significantly inhibited by both inhibitors. In vivo, TNFα-induced ROS and inflammation were ameliorated by targeted Nox2 inhibition, which, in turn, improved hind-limb blood flow. These studies identify a proximal role for Nox2 in propagated inflammatory signaling and support therapeutic value of Nox2 inhibitors in inflammatory disease

Exercise Training Prevents the Perivascular Adipose Tissue-induced Aortic Dysfunction with Metabolic Syndrome

The aim of the study was to determine the effects of exercise training on improving the thoracic perivascularadipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syn-drome and its subsequent actions on aortic function.Methods:Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks ofcontrol conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the inter-vention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a forcetransducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function wereassessed.Results:The mainfindings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) agreater abundance of•NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVATproteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised leanand obese groups vs. controls (p \u3c 0.05). Lean control tPVAT improved aortic relaxation, whereas obese controltPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the leanEx-tPVAT did not affect aortic dilation.Conclusion:Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards anenvironment with less oxidant load, less inflammation and improved proteasome function. Such beneficialchanges to the tPVAT micro-environment with exercise likely played a significant role in mediating the im-provement in aortic function in metabolic syndrome following 8 weeks of exercise

Evaluation of Laminated Veneer Lumber Tensile Strength Using Optical Scanning and Combined Optical-Ultrasonic Techniques

Nondestructive commercial ultrasonic grading provides laminated veneer lumber (LVL) manufacturers a means for sorting veneer based on average ultrasonic propagation time (UPT) and/or average dynamic modulus of elasticity (MOEd). However, little is known about the influence of veneer defects on strength properties of veneer and LVL. Including veneer defect and growth ring pattern measurements, obtained via optical scanning, was hypothesized to improve LVL static tensile strength (Ft) property predictions. Nondestructive and destructive testing of Douglas-fir (Pseudotsuga menziesii) veneer and LVL was performed to evaluate improvements in LVL Ft property predictions. Various models based solely on density, optical, ultrasonic, and combined system measurements were developed for LVL property predictions. LVL static Ft was best predicted (R2 1/4 0.65) with integrated optical and ultrasonic measurements (ie combined system model), which included average defect, growth ring pattern, and MOEd measurements from the LVL material. Results suggested improved LVL Ft predictions could be achieved by integrating ultrasonic and optical systems. Additionally, the optical model, which included average defect, growth ring, and density measurements, better explained the variation in LVL static Ft values (R2 = 0.58) compared with the MOEd (R2 = 0.51) and UPT (R2 = 0.31) models

Improved arterial-ventricular coupling in metabolic syndrome after exercise training: a pilot study

Purpose—The metabolic syndrome (MetS) is associated with a three-fold increase risk of cardiovascular (CV) morbidity and mortality, which is in part, due to a blunted CV reserve capacity, reflected by a reduced peak exercise left ventricular contractility and aerobic capacity, and a blunted peak arterial-ventricular coupling. To date, no study has examined whether aerobic exercise training in MetS can reverse the peak exercise CV dysfunction. Further, examining how exercise training alters CV function in a group of individuals with MetS prior to the development of diabetes and/or overt CVD, can provide insights into whether some of the pathophysiological changes to the CV can be delayed/reversed, lowering their CV risk. The objective of this study was to examine the effects of 8 weeks of aerobic exercise training in individuals with MetS on resting and peak exercise CV function. Methods—Twenty MetS underwent either 8 weeks of aerobic exercise training (MetS-ExT; n=10) or remained sedentary (MetS-NonT; n=10) during this time period. Resting and peak exercise CV function was characterized using Doppler echocardiography and gas exchange. Results—Exercise training did not alter resting left ventricular diastolic or systolic function and arterial-ventricular coupling in MetS. In contrast, at peak exercise an increase in LV contractility (40%, p\u3c0.01), cardiac output (28%, p\u3c0.05) and aerobic capacity (20%, p\u3c0.01), while a reduction in vascular resistance (30%, p\u3c0.05) and arterial-ventricular coupling (27%, p\u3c0.01), were noted in the MetS-ExT but not the MetS-NonT group. Further, an improvement in Lifetime Risk Score was also noted in the MetS-ExT group. Conclusions—These findings have clinical importance as they provide insight that some of the pathophysiological changes associated with MetS can be improved and lower the risk of CVD

Is obesity predictive of cardiovascular dysfunction independent of cardiovascular risk factors? Int J Obes (Lond)

Introduction—Obesity is thought to exert detrimental effects on the cardiovascular (CV) system. However, this relationship is impacted by the co-occurrence of CV risk factors, type II diabetes (T2DM), and overt disease. We examined the relationships between obesity, assessed by body mass index (BMI) and waist circumference (WC), and CV function in 102 subjects without overt CV disease. We hypothesized that obesity would be independently predictive of CV remodeling and functional differences, especially at peak exercise. Methods—Brachial (bSBP) and central (cSBP) systolic pressure, carotid-to-femoral pulse wave velocity (PWVcf) augmentation index (AGI) (by SphygmoCor), and carotid remodeling (B-mode ultrasound) were examined at rest. Further, peak exercise cardiac imaging (Doppler ultrasound) was performed to measure the coupling between the heart and arterial system. Results—In backward elimination regression models, accounting for CV risk factors, neither BMI nor WC were predictors of carotid thickness or PWVcf; rather age, triglycerides, and hypertension were the main determinants. However, BMI and WC predicted carotid crosssectional area and lumen diameter. When examining the relationship between body size and SBP, BMI (β=0.32) and WC (β=0.25) were predictors of bSBP (p \u3c0.05), whereas, BMI was the only predictor of cSBP (β=0.22, p\u3c0.05) indicating a differential relationship between cSBP, bSBP and body size. Further, BMI (β=−0.26) and WC (β=−0.27) were independent predictors of AGI (p\u3c0.05). As for resting cardiac diastolic function, WC seemed to be a better predictor than BMI. However, both BMI and WC were inversely and independently related to arterial elastance (net arterial load) and end-systolic elastance (cardiac contractility) at rest and peak exercise. Discussion—These findings illustrate that obesity, without T2DM and overt CV disease, and after accounting for CV risk factors, is susceptible to pathophysiological adaptations that may predispose individuals to an increased risk of CV events