THE IMPACT OF POSTTRAUMATIC STRESS DISORDER ON PERIPHERAL VASCULAR FUNCTION

The physiological manifestations of posttraumatic stress disorder (PTSD) have been associated with an increase in risk of cardiovascular disease (CVD) independent of negative lifestyle factors. Peripheral vascular dysfunction may be a mechanism by which PTSD increases CVD risk via increases in oxidative stress, inflammation, and/or sympathetic nervous system activity. PURPOSE: This study sought to examine peripheral vascular function in those with PTSD compared to age-matched controls. METHODS: Eight individuals with PTSD (5 women, 3 men; age 22 ± 2 years), and sixteen healthy controls (CON; 10 women, 6 men, 23 ± 2 years), participated in the study. Leg vascular function was assessed via passive leg movement (PLM) technique and evaluated with Doppler ultrasonography. PLM-induced increases in leg blood flow were quantified as peak change in blood flow from baseline (ΔPeak LBF) and blood flow area under the curve (LBF AUC). RESULTS: Significant differences in leg vascular function were revealed between groups. The PTSD group reported significantly lower ΔPeak LBF (PTSD: 294.16 ± 54.16; CON: 594.78 ± 73.70 ml∙min-1; p = 0.01) and LBF AUC (PTSD: 57.23 ± 24.37; CON: 169.92 ± 29.84 ml; p = 0.02) when compared to the CON group. CONCLUSION: This study revealed that lower limb vascular function is impaired in individuals with PTSD when compared to healthy counterparts.https://scholarscompass.vcu.edu/gradposters/1043/thumbnail.jp

Vascular Dysfunction and Posttraumatic Stress Disorder: Examining the Role of Oxidative Stress and Sympathetic Activity

Purpose: The physiological manifestations of posttraumatic stress disorder (PTSD) have been associated with an increase in risk of cardiovascular disease (CVD) independent of negative lifestyle factors. The goal of the study was to better elucidate the mechanisms behind the increased CVD risk by examining peripheral vascular function, a precursor to CVD. Moreover, this study sought to determine the role of oxidative stress and sympathetic nervous system (SNS) activity in PTSD-induced vascular dysfunction. Methods: Sixteen individuals with PTSD (10 women, 6 men; age 24 ± 4 years), and twenty-four healthy controls (CTRL; 15 women, 9 men, 24 ± 4 years), participated in the study. The PTSD group participated in two visits, consuming either a placebo or antioxidant cocktail (AO - vitamins C and E and alpha lipoic acid) prior to their visits, in a randomized order. Arm vascular function was assessed via the reactive hyperemia- induced flow mediated dilation of the brachial artery (BAFMD) technique and evaluated with Doppler ultrasonography. Brachial artery and arm microvascular function were determined by percent change of diameter from baseline normalized for BA shear rate (BAD/Shear), and blood flow area under the curve (BF AUC), respectively. Heart rate variability (HRV) was used to assess autonomic nervous system activity. Results: BF AUC was significantly lower (p = 0.02) and SNS activity was significantly higher (p = 0.02) in the PTSD group when compared to the CTRL group. BAD/Shear was not different between groups. Following the acute AO supplementation, BF AUC was augmented to which it was no longer significantly different (p = 0.16) when compared to the CTRL group. SNS activity within the PTSD group was significantly reduced (p=.007) following the AO supplementation when compared to the PL condition, and the difference between PTSD and CTRL was no longer significant (p=.41). Conclusion: Young individuals with PTSD demonstrated lower arm microvascular, but not brachial artery, function as well as higher sympathetic activity when compared to healthy controls matched for age, sex, and physical activity level. Furthermore, this microvascular dysfunction and SNS activity was attenuated by an acute AO supplementation to the level of the healthy controls. Taken together, this study revealed that the modulation of oxidative stress, via an acute AO supplementation, improved vascular dysfunction in individuals with PTSD, potentially by reducing the substantial SNS activity associated with this disorder.https://scholarscompass.vcu.edu/gradposters/1084/thumbnail.jp

Effects of Dietary Sodium Intake on Blood Flow Regulation During Exercise in Salt Resistant Individuals

PURPOSE: Dietary sodium intake guidelines is ≤2,300 mg/day, yet is exceeded by 90% of Americans. This study examined the impact of a high sodium diet on blood flow regulation during exercise. METHODS: Six males (25 ± 2 years) consumed dietary sodium intake guidelines for two weeks, with one week salt-capsule supplemented (HS: 6,900 mg/day of sodium) and the other week placebo-capsule supplemented (LS: 2,300 mg/day of sodium). At the end of each week, peripheral hemodynamic measurements [blood flow (BF), shear rate (SR), and flow mediated dilation (FMD)/SR)] of the brachial and superficial femoral artery were taken during handgrip (HG) and plantar flexion (PF) exercise, respectively. Each exercise workload was 3 minutes and progressed by 8 kilograms until exhaustion. RESULTS: There were no differences between LS and HS in blood pressure (82 ± 4 v 80 ± 5 mmHg; p = 0.3) or heart rate (56 ± 6 v 59 ± 10 bpm; p = 0.4). HG and PF exercise increased BF, SR, and FMD/SR across workload (p \u3c 0.03 for all), but no difference between diets (p \u3e 0.05 for all). CONCLUSION: Despite previous reports that HS impairs resting vascular function, this study revealed that peripheral vascular function and blood flow regulation during exercise is not impacted by a HS diet.https://scholarscompass.vcu.edu/gradposters/1082/thumbnail.jp

Selective amyloid-β lowering agents

The amyloid-β peptide (Aβ), implicated in the pathogenesis of Alzheimer's disease (AD), is produced through sequential proteolysis of the Aβ precursor protein (APP) by β- and γ-secretases. Thus, blocking either of these two proteases, directly or indirectly, is potentially worthwhile toward developing AD therapeutics. β-Secretase is a membrane-tethered pepsin-like aspartyl protease suitable for structure-based design, whereas γ-secretase is an unusual, heterotetrameric membrane-embedded aspartyl protease. While γ-secretase inhibitors entered clinical trials first due to their superior pharmacological properties (for example, brain penetration) over β-secretase inhibitors, it has since become clear that γ-secretase inhibitors can cause mechanism-based toxicities owing to interference with the proteolysis of another γ-secretase substrate, the Notch receptor. Strategies for targeting Aβ production at the γ-secretase level without blocking Notch signalling will be discussed. Other strategies utilizing cell-based screening have led to the identification of novel Aβ lowering agents that likewise leave Notch proteolysis intact. The mechanism by which these agents lower Aβ is unknown, but these compounds may ultimately reveal new targets for AD therapeutics

Automated Generation of High-Order Modes for Tests of Quasi-Optical Systems of Gyrotrons for W7-X Stellarator

A test system for the verification of the quasi-optical converter system is vital in the gyrotron development. For this reason, an automated measurement setup has been developed and is benchmarked with the TE$_{28,8}$ mode operating in the cavities of the gyrotrons of W7-X with a high purity of about 95 % and a counter-rotating amount of about 0.3 %. The time duration for the mode generator adjustment has been reduced to two days for this mode. After a successful mode excitation, the quasi-optical mode converter, consisting of a launcher and three mirrors, is measured having a vectorial Gaussian mode content of 97 %

Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site

γ-Secretase generates the peptides of Alzheimer's disease, Aβ40 and Aβ42, by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, changing the Aβ42/Aβ40 ratio, and are thus a promising therapeutic approach for Alzheimer's disease. However, the target for γ-secretase modulators is uncertain, with some data suggesting that they function on γ-secretase, whereas others support their binding to the amyloid precursor. In this paper we address this controversy by using a fluorescence resonance energy transfer-based assay to examine whether γ-secretase modulators alter Presenilin-1/γ-secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. We report that the γ-secretase allosteric site is located within the γ-secretase complex, but substrate docking is needed for γ-secretase modulators to access this site

Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex