Redox-Regulation of α-Globin in Vascular Physiology

Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe2+) α-globin to the oxidized (Fe3+) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe3+) α-globin must be stabilized and recycled to (Fe2+) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe3+) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe3+) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b5 reductase (CyB5R3) with cytochrome b5 type A (CyB5a) can reduce (Fe3+) α-globin in solution. Here, we examine the expression and cellular localization of eNOS, CyB5a, and CyB5R3 in mouse arterial ECs and show that α-globin can be reduced by either of two independent redox systems, CyB5R3/CyB5a and eNOS. Together, our findings provide new insights into the regulation of blood vessel contractility.

Abnormal sympathetic neural recruitment patterns and hemodynamic responses to cold pressor test in women with posttraumatic stress disorder

The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.

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OBJECTIVES/SPECIFIC AIMS: To assess the association between probable OSA and the sudden unexpected death in epilepsy (SUDEP-7) risk profiling index in monitored adult inpatients with epilepsy. METHODS/STUDY POPULATION: We analyzed 49 consecutive adults (>18 years) with refractory epilepsy admitted to our inpatient epilepsy monitoring unit. The SUDEP-7 inventory was performed for all subjects. Probable OSA was identified using overnight oximetry, the Sleep Apnea Sleep Disorder Questionnaire (SA-SDQ), and STOP-BANG inventory. RESULTS/ANTICIPATED RESULTS: Thirty-nine percent of participants screened positive for probable sleep apnea. Patients with high SUDEP-7 scores were more likely to have a positive screen for OSA. DISCUSSION/SIGNIFICANCE OF IMPACT: OSA is an independent risk factor for sudden cardiac death. OSA may be a hitherto unrecognized contributor to sudden death risk in epilepsy. Further studies determining the relationship between OSA, neural circulatory control and SUDEP are warranted.