Erythrocytes and Vascular Function: Oxygen and Nitric Oxide

Erythrocytes regulate vascular function through the modulation of oxygen delivery and the scavenging and generation of nitric oxide (NO). First, hemoglobin inside the red blood cell binds oxygen in the lungs and delivers it to tissues throughout the body in an allosterically regulated process, modulated by oxygen, carbon dioxide and proton concentrations. The vasculature responds to low oxygen tensions through vasodilation, further recruiting blood flow and oxygen carrying erythrocytes. Research has shown multiple mechanisms are at play in this classical hypoxic vasodilatory response, with a potential role of red cell derived vasodilatory molecules, such as nitrite derived nitric oxide and red blood cell ATP, considered in the last 20 years. According to these hypotheses, red blood cells release vasodilatory molecules under low oxygen pressures. Candidate molecules released by erythrocytes and responsible for hypoxic vasodilation are nitric oxide, adenosine triphosphate and S-nitrosothiols. Our research group has characterized the biochemistry and physiological effects of the electron and proton transfer reactions from hemoglobin and other ferrous heme globins with nitrite to form NO. In addition to NO generation from nitrite during deoxygenation, hemoglobin has a high affinity for NO. Scavenging of NO by hemoglobin can cause vasoconstriction, which is greatly enhanced by cell free hemoglobin outside of the red cell. Therefore, compartmentalization of hemoglobin inside red blood cells and localization of red blood cells in the blood stream are important for healthy vascular function. Conditions where erythrocyte lysis leads to cell free hemoglobin or where erythrocytes adhere to the endothelium can result in hypertension and vaso constriction. These studies support a model where hemoglobin serves as an oxido-reductase, inhibiting NO and promoting higher vessel tone when oxygenated and reducing nitrite to form NO and vasodilate when deoxygenated. How erythrocytes modulate vascular tone has been widely studied over the last two decades. The vasodilation of the vasculature under hypoxic conditions has inspired much research ranging from the effect of oxygen partial pressure on smooth muscle cell contractility and endothelial nitric oxide synthase (eNOS) activity to nitrite reduction by hemoglobin (Hb) inside erythrocytes and subsequent production of nitric oxide. Here we review how red blood cells (RBCs) and hemoglobin regulate vascular function and blood flow

Elevated pulse pressure is associated with hemolysis, proteinuria and chronic kidney disease in sickle cell disease

A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n 5 661) enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta 5 2.37, p 5 0.02) and high hemolytic index (beta 5 1.53, p50.002) in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta 5 3.21, p 5 0.02), and with proteinuria (beta 5 2.52, p 5 0.04). These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses

Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.Fil: Kelley, Eric E.. University of Pittsburgh; Estados UnidosFil: Baust, Jeff. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Golin Bisello, Franca. University of Pittsburgh; Estados UnidosFil: Devlin, Jason E.. University of Pittsburgh; Estados UnidosFil: Croix, Claudette M. St.. University of Pittsburgh; Estados UnidosFil: Watkins, Simon C.. University of Pittsburgh; Estados UnidosFil: Gor, Sonia. University of Pittsburgh; Estados UnidosFil: Cantu Medellin, Nadiezhda. University of Pittsburgh; Estados UnidosFil: Weidert, Eric R.. University of Pittsburgh; Estados UnidosFil: Frisbee,Jefferson C.. University of Virginia; Estados UnidosFil: Gladwin, Mark T.. University of Pittsburgh; Estados UnidosFil: Champion, Hunter C.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Khoo, Nicholas K.H.. University of Pittsburgh; Estados Unido

Mechanism of faster NO scavenging by older stored red blood cells

The blood storage lesion involves morphological and biochemical changes of red blood cells (RBCs) that occur during storage. These include conversion of the biconcave disc morphology to a spherical one, decreased mean corpuscular hemoglobin concentration, varied mean corpuscular volume, reduced integrity of the erythrocyte membrane with formation of microparticles, and increased cell-free hemoglobin. We studied the extent that older stored red blood cells scavenge nitric oxide (NO) faster than fresher stored red blood cells. Using electron paramagnetic resonance spectroscopy and stopped-flow absorption spectroscopy to measure the rate of NO uptake and reaction with hemoglobin in red cells, we found that older stored red blood cells scavenge NO about 1.8 times faster than fresher ones. Based on these experimental data, we simulated NO scavenging by fresher or older stored red blood cells with a biconcave or spherical geometry, respectively, in order to explore the mechanism of NO scavenging related to changes that occur during blood storage. We found that red blood cells with a spherical geometry scavenges NO about 2 times slower than ones with a biconcave geometry, and a smaller RBC hemoglobin concentration or volume increases NO scavenging by red blood cells. Our simulations demonstrate that even the most extreme possible changes in mean corpuscular hemoglobin concentration and mean corpuscular volume that favor increased NO scavenging are insufficient to account for what is observed experimentally. Therefore, RBC membrane permeability must increase during storage and we find that the permeability is likely to increase between 5 and 70 fold. Simulations using a two-dimensional blood vessel show that even a 5-fold increase in membrane permeability to NO can reduce NO bioavailability at the smooth muscle. Background: Transfusion of older stored blood may be harmful. Results: Older stored red blood cells scavenge nitric oxide more than fresher cells. Conclusion: As stored red blood cells age, structural and biochemical changes occur that lead to faster scavenging. Significance: Increased nitric oxide scavenging by red blood cells as a function of storage age contributes to deleterious effects upon transfusion. © 2014 The Authors

Elevated n-terminal pro-brain natriuretic peptide is associated with mortality in tobacco smokers independent of airflow obstruction

Background: Tobacco use is associated with an increased prevalence of cardiovascular disease. N-terminal pro-brain natiuretic peptide (NT-proBNP), a widely available biomarker that is associated with cardiovascular outcomes in other conditions, has not been investigated as a predictor of mortality in tobacco smokers. We hypothesized that NT-proBNP would be an independent prognostic marker in a cohort of well-characterized tobacco smokers without known cardiovascular disease. Methods: Clinical data from 796 subjects enrolled in two prospective tobacco exposed cohorts was assessed to determine factors associated with elevated NT-proBNP and the relationship of these factors and NT-proBNP with mortality. Results: Subjects were followed for a median of 562 (IQR 252 - 826) days. Characteristics associated with a NT-proBNP above the median (≥49 pg/mL) were increased age, female gender, and decreased body mass index. By time-to-event analysis, an NT-proBNP above the median (≥49 pg/mL) was a significant predictor of mortality (log rank p = 0.02). By proportional hazard analysis controlling for age, gender, cohort, and severity of airflow obstruction, an elevated NT-proBNP level (≥49 pg/mL) remained an independent predictor of mortality (HR = 2.19, 95% CI 1.07-4.46, p = 0.031). Conclusions: Elevated NT-proBNP is an independent predictor of mortality in tobacco smokers without known cardiovascular disease, conferring a 2.2 fold increased risk of death. Future studies should assess the ability of this biomarker to guide further diagnostic testing and to direct specific cardiovascular risk reduction inventions that may positively impact quality of life and survival. © 2011 Stamm et al

Exact quantization of a PT-symmetric (reversible) Li\'enard-type nonlinear oscillator

We carry out an exact quantization of a PT symmetric (reversible) Li\'{e}nard type one dimensional nonlinear oscillator both semiclassically and quantum mechanically. The associated time independent classical Hamiltonian is of non-standard type and is invariant under a combined coordinate reflection and time reversal transformation. We use von Roos symmetric ordering procedure to write down the appropriate quantum Hamiltonian. While the quantum problem cannot be tackled in coordinate space, we show how the problem can be successfully solved in momentum space by solving the underlying Schr\"{o}dinger equation therein. We obtain explicitly the eigenvalues and eigenfunctions (in momentum space) and deduce the remarkable result that the spectrum agrees exactly with that of the linear harmonic oscillator, which is also confirmed by a semiclassical modified Bohr-Sommerfeld quantization rule, while the eigenfunctions are completely different.Comment: 10 pages, 1 figure, Fast Track Communicatio

Effects of appraisal training on responses to a distressing autobiographical event

Dysfunctional appraisals are a key factor suggested to be involved in the development and maintenance of PTSD. Research has shown that experimental induction of a positive or negative appraisal style following a laboratory stressor affects analogue posttraumatic stress symptoms. This supports a causal role of appraisal in the development of traumatic stress symptoms and the therapeutic promise of modifying appraisals to reduce PTSD symptoms. The present study aimed to extend previous findings by investigating the effects of experimentally induced appraisals on reactions to a naturally occurring analogue trauma and by examining effects on both explicit and implicit appraisals. Participants who had experienced a distressing life event were asked to imagine themselves in the most distressing moment of that event and then received either a positive or negative Cognitive Bias Modification training targeting appraisals (CBM-App). The CBM-App training induced training-congruent appraisals, but group differences in changes in appraisal over training were only seen for explicit and not implicit appraisals. However, participants trained positively reported less intrusion distress over the subsequent week than those trained negatively, and lower levels of overall posttraumatic stress symptoms. These data support the causal relationship between appraisals and trauma distress, and further illuminate the mechanisms linking the two

Exact solutions of coupled Li\'enard-type nonlinear systems using factorization technique

General solutions of nonlinear ordinary differential equations (ODEs) are in general difficult to find although powerful integrability techniques exist in the literature for this purpose. It has been shown that in some scalar cases particular solutions may be found with little effort if it is possible to factorize the equation in terms of first order differential operators. In our present study we use this factorization technique to address the problem of finding solutions of a system of general two-coupled Li\'enard type nonlinear differential equations. We describe a generic algorithm to identify specific classes of Li\'enard type systems for which solutions may be found. We demonstrate this method by identifying a class of two-coupled equations for which the particular solution can be found by solving a Bernoulli equation. This class of equations include coupled generalization of the modified Emden equation. We further deduce the general solution of a class of coupled ordinary differential equations using the factorization procedure discussed in this manuscript.Comment: Accepted for publication in J. Math. Phy

Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe

Although recent studies show an improved survival of children with sickle cell disease in the US and Europe, for adult patients mortality remains high. This study was conducted to evaluate the factors associated with mortality in adult patients following the approval of hydroxyurea. We first evaluated the association between selected variables and mortality at an academic center (University of North Carolina). Data sources were then searched for publications from 1998 to June 2016, with meta-analysis of eligible studies conducted in North America and Europe to evaluate the associations of selected variables with mortality in adult patients. Nine studies, combined with the UNC cohort (total n=3257 patients) met the eligibility criteria. Mortality was significantly associated with age (per 10-year increase in age) [7 studies, 2306 participants; hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.10–1.50], tricuspid regurgitant jet velocity 2.5 m/s or more (5 studies, 1577 participants; HR: 3.03; 95%CI: 2.0–4.60), reticulocyte count (3 studies, 1050 participants; HR: 1.05; 95%CI: 1.01–1.10), log(N-terminal-pro-brain natriuretic peptide) (3 studies, 800 participants; HR: 1.68; 95%CI: 1.48–1.90), and fetal hemoglobin (7 studies, 2477 participants; HR: 0.97; 95%CI: 0.94–1.0). This study identifies variables associated with mortality in adult patients with sickle cell disease in the hydroxyurea era

A novel genetic programming approach to the design of engine control systems for the voltage stabilisation of hybrid electric vehicle generator outputs

This paper describes a Genetic Programming based automatic design methodology applied to the maintenance of a stable generated electrical output from a series-hybrid vehi- cle generator set. The generator set comprises a 3-phase AC generator whose output is subsequently rectified to DC.The engine/generator combination receives its control input via an electronically actuated throttle, whose control integration is made more complex due to the significant system time delay. This time delay problem is usually addressed by model predictive design methods, which add computational complexity and rely as a necessity on accurate system and delay models. In order to eliminate this reliance, and achieve stable operation with disturbance rejection, a controller is designed via a Genetic Programming framework implemented directly in Matlab, and particularly, Simulink. the principal objective is to obtain a relatively simple controller for the time-delay system which doesn’t rely on computationally expensive structures, yet retains inherent disturabance rejection properties. A methodology is presented to automatically design control systems directly upon the block libraries available in Simulink to automatically evolve robust control structures