Vascular endothelial growth factor (VEGF) and its two endothelial cell-specific receptor tyrosine kinases, Flk-1/KDR and Flt-1, play a key role in physiological and pathological angiogenesis. Hypoxia has been shown to be a major mechanism for up-regulation of VEGF and its receptors in vivo. When we exposed human umbilical vein endothelial cells to hypoxic conditions in vitro, we observed increased levels of Flt-1 expression. In contrast, Flk-1/KDR mRNA levels were unchanged or slightly repressed. These findings suggest a differential transcriptional regulation of the two receptors by hypoxia. To identify regulatory elements involved in the hypoxic response, promoter regions of the mouse Flt-1 and Flk-1/KDR genes were isolated and tested in conjunction with luciferase reporter gene. In transient transfection assays, hypoxia led to strong transcriptional activation of the Flt-1 promoter, whereas Flk-1/ KDR transcription was essentially unchanged. Promoter deletion analysis demonstrated a 430-bp region of the Flt-1 promoter to be required for transcriptional activation in response to hypoxia. This region includes a heptamer sequence matching the hypoxia-inducible factor-1 (HIF) consensus binding site previously found in other hypoxia-inducible genes such as the VEGF gene and erythropoietin gene. We further narrowed down the element mediating the hypoxia response to a 40-base pair sequence including the putative HIF binding site. We show that this element acts like an enhancer, since it activated transcription irrespective of its location or orientation in the construct. Furthermore, mutations within the putative HIF consensus binding site lead to impaired transcriptional activation by hypoxia. These findings indicate that, unlike the KDR/Flk-1 gene, the Flt-1 receptor gene is directly up-regulated by hypoxia via a hypoxia-inducible enhancer element located at positions ؊976 to ؊937 of the Flt-1 promoter.
This review summarizes the detrimental effects of cigarette and noncigarette emission exposure on autonomic function, with particular emphasis on the mechanisms of acute and chronic modulation of the sympathetic nervous system. We propose that the nicotine and fine particulate matter in tobacco smoke lead to increased sympathetic nerve activity, which becomes persistent via a positive feedback loop between sympathetic nerve activity and reactive oxidative species. Furthermore, we propose that baroreflex suppression of sympathetic activation is attenuated in habitual smokers; that is, the baroreflex plays a permissive role, allowing sympathoexcitation to occur without restraint in the setting of increased pressor response. This model is also applicable to other nontobacco cigarette emission exposures (e.g., marijuana, waterpipes [hookahs], electronic cigarettes, and even air pollution). Fortunately, emerging data suggest that baroreflex sensitivity and autonomic function may be restored after smoking cessation, providing further evidence in support of the health benefits of smoking cessation.
Key pointsr Patients with post-traumatic stress disorder (PTSD) are at a significantly higher risk of developing hypertension and cardiovascular disease. The mechanisms underlying this increased risk are not known.r Studies have suggested that PTSD patients have an overactive sympathetic nervous system (SNS) that could contribute to cardiovascular risk; however, sympathetic function has not previously been rigorously evaluated in PTSD patients.r Using direct measurements of sympathetic nerve activity and pharmacological manipulation of blood pressure, we show that veterans with PTSD have augmented SNS and haemodynamic reactivity during both combat-related and non-combat related mental stress, impaired sympathetic and cardiovagal baroreflex sensitivity, and increased inflammation.r Identifying the mechanisms contributing to increased cardiovascular (CV) risk in PTSD will pave the way for developing interventions to improve sympathetic function and reduce CV risk in these patients.Abstract Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular (CV) risk. We tested the hypothesis that PTSD patients have augmented sympathetic nervous system (SNS) and haemodynamic reactivity during mental stress, as well as impaired arterial baroreflex sensitivity (BRS). Fourteen otherwise healthy Veterans with combat-related PTSD were compared with 14 matched Controls without PTSD. Muscle sympathetic nerve activity (MSNA), continuous blood pressure (BP) and electrocardiography were measured at baseline, as well as during two types of mental stress: combat-related mental stress using virtual reality combat exposure (VRCE) and non-combat related stress using mental arithmetic (MA). A cold pressor test (CPT) was administered for comparison. BRS was tested using pharmacological manipulation of BP via the Modified Oxford technique at rest and during VRCE. Blood samples were analysed for inflammatory biomarkers. Baseline characteristics, MSNA and haemodynamics were similar between the groups. In PTSD vs. Controls, MSNA (+8.2 ± 1.0 vs. +1.2 ± 1.3 bursts min -1 , P < 0.001) and heart rate responses (+3.2 ± 1.1 vs. −2.3 ± 1.0 beats min -1 , P = 0.003) were significantly augmented during VRCE. Similarly, in PTSD vs. Controls, MSNA (+21.0 ± 2.6 vs. +6.7 ± 1.5 bursts min -1 , P < 0.001) and diastolic BP responses (+6.3 ± 1.0 vs. +3.5 ± 1.0 mmHg, P = 0.011) were significantly augmented during MA but not during CPT (P = not significant). In the PTSD group, sympathetic BRS (-1.2 ± 0.2 vs. -2.0 ± 0.3 burst incidence mmHg and cardiovagal BRS (9.5 ± 1.4 vs. 23.6 ± 4.3 ms mmHg −1 , P = 0.008) were significantly blunted at rest. PTSD patients had significantly higher highly sensitive-C-reactive protein levels compared to Controls (2.1 ± 0.4 vs. 1.0 ± 0.3 mg L −1 , P = 0.047). Augmented SNS and haemodynamic responses to mental stress, blunted BRS and inflammation may contribute to an increased CV risk in PTSD.
The kinetics of the metathetical reaction of phenyl radical with methane has been studied theoretically and experimentally. The rate constants determined by two complementary methods, pyrolysis/Fourier transform infrared spectrometry and pulsed laser photolysis/mass spectrometry in the temperature range 600-980 K, give the Arrhenius equation: k 1 ) 10 12.78 ( 0.13 exp[(-6201 ( 225)/T] cm 3 /(mol s). At the best theoretical level employed (G2M(CC,MP2)), the barrier for the reaction at 0 K is E 1 0 ) 9.3 kcal/mol. The rate constant k 1 calculated from theoretical molecular parameters fits experimental data if the barrier height is increased to 10.5 kcal/mol. The fitted barrier is well within the 2-3 kcal/mol accuracy of the G2M method for the present open-shell, seven-heavy-atom system. Because of the relatively high reaction barrier and the predicted high imaginary frequency (1551 cm -1 ), tunneling corrections resulted in a significant enhancement in the calculated rate constant, 150% at 500 K and 7% at 2000 K. The theoretical result also correlates well with recently reported shock-tube data measured in the temperature range 1050-1450 K by UV absorption spectrometry. Kinetic analysis of the toluene formation data obtained from the photolysis of acetophenone without and with added H 2 and CH 4 gave the rate constant for the recombination of CH 3 and C 6 H 5 , k 2 ) (1.38 ( 0.08) × 10 13 exp [-(23 ( 36)/T] cm 3 /(mol s) for the temperature range 300-980 K.
-Stressand anxiety-related disorders are on the rise in both military and general populations. Over the next decade, it is predicted that treatment of these conditions, in particular, posttraumatic stress disorder (PTSD), along with its associated longterm comorbidities, will challenge the health care system. Multiple organ systems are adversely affected by PTSD, and PTSD is linked to cancer, arthritis, digestive disease, and cardiovascular disease. Evidence for a strong link between PTSD and cardiovascular disease is compelling, and this review describes current clinical data linking PTSD to cardiovascular disease, via inflammation, autonomic dysfunction, and the renin-angiotensin system. Recent clinical and preclinical evidence regarding the role of the renin-angiotensin system in the extinction of fear memory and relevance in PTSD-related immune and autonomic dysfunction is also addressed. posttraumatic stress disorder; cardiovascular disease; renin-angiotensin system POSTTRAUMATIC STRESS DISORDER (PTSD) is a psychiatric illness characterized by persistent emotional and mental stress following a traumatic event. Symptoms of PTSD include hyperarousal, flashbacks, intrusive thoughts, or nightmares, and avoidance of activities that trigger memories of the traumatic event. The health consequences of PTSD are substantial, affecting multiple organ systems, with evidence linking PTSD to diseases such as cancer, arthritis, digestive disease, and cardiovascular disease (CVD) (13,14,112). The evidence demonstrating increased risk for CVD in PTSD (9,15,19,49,57,58) is compelling, and several excellent recent review articles have highlighted this association (20,23,52,63,112). While this association could certainly be due, in part, to related unhealthy behaviors, such as increased prevalence of smoking, poor diet, and physical inactivity (46,119). Yet even after adjustments for lifestyle, comorbid conditions, and combat engagements in multivariate models, PTSD remains a significant and independent risk factor for the development of CVD and CVD-related mortality (15).Increased CVD risk in PTSD has been demonstrated in both military (21) and civilian populations (44,82). A co-twin study design (monozygotic and dizygotic), which controlled for genetic and familial confounders, demonstrated that the incidence of coronary heart disease was more than double in Vietnam War veteran twins with PTSD (22.6%) compared with those without PTSD (8.9%) (106). Most recently, one of the largest longitudinal studies examining the association between PTSD and heart failure was completed, and veterans with PTSD were shown to be nearly 50% more likely to develop heart failure than veterans without PTSD (91). This remained significant after adjustments for age, sex, diabetes, hyperlipidemia, hypertension, body mass index, combat, and military service. Civilian PTSD populations are also at greater risk for CVD. Following life-threatening traumatic events such as earthquakes (82), the 9 -11 World Trade Center attack (45), and living in urban dis...
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