Browsing by Subject "endothelial dysfunction"
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Item Associations between affective traits and endothelial function in depressed adults(2018) Berntson, Jessica; Stewart, Jesse C.; Cyders, Melissa A.; Rand, Kevin L.; Gupta, Samir K.Depressed adults are at increased risk of developing atherosclerotic cardiovascular disease (CVD). However, heterogeneity in the depressed population engenders a key question: Are there subgroups of depressed adults at greater risk of developing CVD? Because other affective traits – i.e., anxiety, hostility/anger, and low trait positive affect – have also been associated with increased CVD risk, depressed adults with higher levels of these co-occurring affective traits may have an elevated risk of developing CVD. Consequently, the present study’s first aim was to examine, in depressed adults, which affective traits (depression, anxiety, hostility/anger, or low positive affect) are associated with endothelial function, a marker of cumulative CVD risk. In addition, because the other affective traits overlap with depressive symptom severity, this study’s second aim was to investigate which components of pairs of affective traits (shared versus unique) are related to endothelial function. Finally, given that the mechanisms underlying affective trait-endothelial function relationships in depressed adults are unknown, this study’s third aim was to explore traditional CVD risk status as a candidate mediator of observed relationships. To achieve these aims, I combined pre-treatment, cross-sectional data from three randomized controlled trials involving 138 depressed primary care patients with no history of clinical CVD. Assessments included validated self-report questionnaires for affective traits, brachial artery flow-mediated dilation (FMD) for endothelial function, and 10-year Framingham risk score for traditional CVD risk status. I conducted structural equation modeling (SEM) with confirmatory factor analysis to examine the relationships of interest after adjusting for age, sex, race/ethnicity, education, and baseline arterial diameter. Although the shared variance between each affective trait pair could not be modeled due to poor fit, adequate fitting models revealed that hostility/anger and the unique components of hostility/anger were associated with poorer endothelial function (standardized coefficients = -.18 and -.22, respectively). All of the other affective traits and their components (depression, anxiety, positive affect, unique depression, unique anxiety, and unique positive affect) were not related to endothelial function (all ps > .08). Traditional CVD risk status did not partially explain the relationship between the unique components of hostility/anger and endothelial function (standardized coefficient for the indirect effect = .00; p = .89). If my results are supported by future findings, it would suggest that depressed adults with hostility/anger (a) may be a subgroup of the depressed population at greater risk of developing CVD and (b) may be in need of earlier, more intense, and/or different CVD primary prevention efforts. Future studies are needed to confirm this relationship and identify underlying mechanisms.Item HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction Implications for Statin Treatment in HIV Patients(American Heart Association, 2019-08-27) Chelvanambi, Sarvesh; Gupta, Samir K.; Chen, Xingjuan; Ellis, Bradley W.; Maier, Bernhard F.; Colbert, Tyler M.; Kuriakose, Jithin; Zorlutuna, Pinar; Jolicoeur, Paul; Obukhov, Alexander G.; Clauss, Matthias; Medicine, School of MedicineRationale Even in antiretroviral therapy (ART) treated patients, HIV continues to play a pathogenic role in cardiovascular diseases. A possible cofactor may be persistence of the early HIV response gene Nef, which we have demonstrated recently to persist in the lungs of HIV+ patients on ART. Previously, we have reported that HIV strains with Nef, but not Nef-deleted HIV strains, cause endothelial proinflammatory activation and apoptosis. Objective To characterize mechanisms through which HIV-Nef leads to the development of cardiovascular diseases using ex vivo tissue culture approaches as well as interventional experiments in transgenic murine models. Methods and Results EV (extracellular vesicles) derived from both peripheral blood mononuclear cells (PBMC) and plasma from HIV+ patient blood samples induced human coronary artery endothelial cells dysfunction. Plasma derived EV from ART+ patients that were HIV-Nef+ induced significantly greater endothelial apoptosis compared to HIV-Nef- plasma EV. Both HIV-Nef expressing T cells and HIV-Nef-induced EV increased transfer of cytosol and Nef protein to endothelial monolayers in a Rac1-dependent manner, consequently leading to endothelial adhesion protein upregulation and apoptosis. HIV-Nef induced Rac1 activation also led to dsDNA breaks in endothelial colony forming cells (ECFC), thereby resulting in ECFC premature senescence and eNOS downregulation. These Rac1 dependent activities were characterized by NOX2-mediated ROS production. Statin treatment equally inhibited Rac1 inhibition in preventing or reversing all HIV-Nef-induction abnormalities assessed. This was likely due to the ability of statins to block Rac1 prenylation as geranylgeranyl transferase inhibitors were effective in inhibiting HIV-Nef-induced ROS formation. Finally, transgenic expression of HIV-Nef in endothelial cells in a murine model impaired endothelium-mediated aortic ring dilation, which was then reversed by 3-week treatment with 5mg/kg atorvastatin. Conclusion These studies establish a mechanism by which HIV-Nef persistence despite ART could contribute to ongoing HIV related vascular dysfunction which may then be ameliorated by statin treatment.Item Insomnia and mechanistic pathways to atherosclerotic CVD in HIV(2020-08) Polanka, Brittanny M.; Stewart, Jesse; Zapolski, Tamika; Hirsh, Adam; Gupta, SamirStudy 1: Background: Insomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated. Methods: We examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people living with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, “Difficulty falling or staying asleep?,” with the following response options: “I do not have this symptom” or “I have this symptom and…” “it doesn’t bother me,” “it bothers me a little,” “it bothers me,” “it bothers me a lot.” Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval (CI). Results: For sCD14 and D-dimer, we observed no significant associations. For IL-6, veterans in the “bothers a lot” group had 15% higher IL-6 than veterans in the “I do not have this symptom” group in the demographic-adjusted model (exp[b]=1.15, 95%CI=1.02-1.29, p=.03). This association was nonsignificant in the fully-adjusted model (exp[b]=1.07, 95%CI=0.95-1.19, p=.25). Conclusion: We observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted. Study 2: Background: While insomnia has been identified as a potential risk factor for cardiovascular disease in HIV (HIV-CVD), research on the underlying pathophysiological mechanisms is scarce. Methods: We examined associations between 0-to-12-week changes in sleep disturbance and the concurrent 0-to-12-week changes and the subsequent 12-to-24-week changes in markers of systemic inflammation, coagulation, and endothelial dysfunction among people living with HIV (n = 33-38) enrolled in a depression clinical trial. Sleep disturbance was measured using the Pittsburgh Sleep Quality Index. Inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) and coagulation marker D-dimer were determined from blood specimens; endothelial dysfunction marker brachial flow-mediated dilation (FMD) was determined by ultrasound. 0-to-12-week variables were calculated as 12-week visit minus baseline, and 12-to-24-week variables were calculated as 24-week minus 12-week. We constructed multivariate linear regression models for each outcome adjusting for age, sex, race/ethnicity, Framingham risk score, and baseline depressive symptoms. Results: We did not observe statistically significant associations between 0-to-12-week changes in sleep disturbance and 0-to-12-week or 12-to-24-week changes in IL-6, CRP, D-dimer, or FMD. However, we did observe potentially meaningful associations, likely undetected due to low power. For 0-to-12-weeks, every 1-standard deviation (SD) increase, or worsening, in the sleep disturbance change score was associated with a 0.41 pg/mL and 80 ng/mL decease in IL-6 and D-dimer, respectively. For 12-to-24-weeks, every 1-SD increase in sleep disturbance change score was associated with a 0.63 mg/L, 111 ng/mL, and 0.82% increase in CRP, D-dimer, and FMD, respectively. Conclusion: We observed potentially meaningful, though not statistically significant, associations between changes in sleep disturbance and changes in biological mechanisms underlying HIV-CVD over time. Some associations were in the expected direction, but others were not. Additional studies are needed that utilize larger samples and validated, comprehensive assessments of insomnia.Item Reactive oxygen species' role in endothelial dysfunction by electron paramagnetic resonance(2013-08-29) Wassall, Cynthia D.; Kemple, Marvin D.; Joglekar, Yogesh; Petrache, Horia; Nageswara Rao, B. D.; Durbin, Stephen M.; Decca, RicardoThe endothelium is a single layer of cells lining the arteries and is involved in many physiological reactions which are responsible for vascular tone. Free radicals are important participants in these chemical reactions in the endothelium. Here we quantify free radicals, ex vivo, in biological tissue with continuous wave electron paramagnetic resonance (EPR). In all of the experiments in this thesis, we use a novel EPR spin trapping technique that has been developed for tissue segments. EPR spin trapping is often considered the ‘gold standard’ in reactive oxygen species (ROS) detection because of its sensitivity and non-invasive nature. In all experiments, tissue was placed in physiological saline solution with 190-mM PBN (N-tert-butyl-α-phenylnitrone), 10% by volume dimethyl-sulphoxide (DMSO) for cryopreservation, and incubated in the dark for between 30 minutes up to 2 hours at 37°C while gently being stirred. Tissue and supernatant were then loaded into a syringe and frozen at -80°C until EPR analysis. In our experiments, the EPR spectra were normalized with respect to tissue volume. Conducting experiments at liquid nitrogen temperature leads to some experimental advantages. The freezing of the spin adducts renders them stable over a longer period, which allows ample time to analyze tissue samples for ROS. The dielectric constant of ice is greatly reduced over its liquid counterpart; this property of water enables larger sample volumes to be inserted into the EPR cavity without overloading it and leads to enhanced signal detection. Due to Maxwell-Boltzmann statistics, the population difference goes up as the temperature goes down, so this phenomenon enhances the signal intensity as well. With the ‘gold standard’ assertion in mind, we investigated whether slicing tissue to assay ROS that is commonly used in fluorescence experiments will show more free radical generation than tissue of a similar volume that remains unsliced. Sliced tissue exhibited a 76% increase in ROS generation; this implies that higher ROS concentrations in sliced tissue indicate extraneous ROS generation not associated with the ROS stimulus of interest. We also investigated the role of ROS in chronic flow overload (CFO). Elevation of shear stress that increases production of vascular ROS has not been well investigated. We hypothesize that CFO increases ROS production mediated in part by NADPH oxidase, which leads to endothelial dysfunction. ROS production increased threefold in response to CFO. The endothelium dependent vasorelaxation was compromised in the CFO group. Treatment with apocynin significantly reduced ROS production in the vessel wall, preserved endothelial function, and inhibited expressions of p22/p47phox and NOX2/NOX4. The present data implicate NADPH oxidase produced ROS and eNOS uncoupling in endothelial dysfunction at 1 wk of CFO. In further work, a swine right ventricular hypertrophy (RVH) model induced by pulmonary artery (PA) banding was used to study right coronary artery (RCA) endothelial function and ROS level. Endothelial function was compromised in RCA of RVH as attributed to insufficient endothelial nitric oxide synthase cofactor tetrahydrobiopterin. In conclusion, stretch due to outward remodeling of RCA during RVH (at constant wall shear stress), similar to vessel stretch in hypertension, appears to induce ROS elevation, endothelial dysfunction, and an increase in basal tone. Finally, although hypertension-induced vascular stiffness and dysfunction are well established in patients and animal models, we hypothesize that stretch or distension due to hypertension and outward expansion is the cause of endothelial dysfunction mediated by angiotensin II type 1 (AT1) receptor in coronary arteries. The expression and activation of AT1 receptor and the production of ROS were up regulated and endothelial function deteriorated in the RCA. The acute inhibition of AT1 receptor and NADPH oxidase partially restored the endothelial function. Stretch or distension activates the AT1 receptor which mediates ROS production; this collectively leads to endothelial dysfunction in coronary arteries.