Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1α expression in normoxic sickle mice: microvascular implications

Abstract

Kaul DK, Fabry ME, Suzuka SM, Zhang X. Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1␣ expression in normoxic sickle mice: microvascular implications. Am J Physiol Heart Circ Physiol 304: H42-H50, 2013. First published November 2, 2012; doi:10.1152/ajpheart.00296.2012.-Chronic inflammation is a salient feature of sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mice. Inflammation is implicated in the activation of hypoxia-inducible factor-1␣ (HIF-1␣) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1␣, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1␣ in normoxic BERK mice expressing exclusively human ␣-and ␤ S -globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., Ͻ1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1␣ is expressed in BERK mice under normoxic conditions, accompanied by increased expression of its vasoactive biomarkers such as VEGF, heme oxygenase-1 (HO-1), and serum ET-1 levels. In BERK mice expressing HbF, HIF-1␣ expression decreases concomitantly with increasing HbF, commensurately with increased NO bioavailability, and shows a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1␣ expression is associated with decreased HO-1, VEGF, and ET-1. Notably, arteriolar dilation, enhanced volumetric blood flow, and low blood pressure in normoxic BERK mice all show a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1␣, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1␣ activation. Thus HIF-1␣ expression in normoxic sickle mice is likely a consequence of chronic inflammation, and HbF exerts an ameliorating effect by decreasing sickling, increasing NO bioavailability, and reducing inflammation. sickle cell disease; hypoxia-inducible factor-1␣; fetal hemoglobin; nitric oxide; oxidative stress; inflammation HEMOGLOBIN S (HBS) polymerization under deoxygenated conditions and abnormal red blood cell rheology are central to the pathophysiology of sickle cell disease (SCD), the consequences of which can lead to vaso-occlusion, reperfusion injury, oxidative stress, hemolysis, reduced nitric oxide (NO) bioavailability, and inflammation (15,19,25,41). In SCD, vaso-occlusive events may result in episodes of tissue ischemia. Tissue ischemia is normally associated with the activation of hypoxia-inducible factor-1␣ (HIF-1␣). Under normoxic conditions, HIF-1␣ expression can be triggered by inflammation (26, 55), a prominent feature of human SCD and transgenic sickle mice (24). Activation of HIF is implicated in cellular adaptive responses to hypoxia and inflammation. HIF can trigger transcription of genes for vasoactive molecules such as vascular endothelial growth factor (VEGF), heme oxygena...

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

“…The VE-cadherin protein concentration in lung homogenates determined by ELISA was lower in the SS NHNrf2−/− mice, consistent with the substantially elevated concentration of the adhesion molecule in the plasma of the same animals (Figure 6C). Previous studies have shown that SpO 2 in nonanesthetized transgenic SS mice is normal at steady state (31, 32), and we confirmed this finding in the SS WT(DL) mice in this study (Figure 7A). The SpO 2 in SS NHNrf2−/− mice was significantly reduced — indicative of oxygen desaturation — coupled to a low breath rate, which suggested that these mice had developed a severe respiratory disease (Figure 7, A and B).…”

Extracellular hemin crisis triggers acute chest syndrome in sickle mice

“…We adopted this approach to monitor SS mice using a validated mouse pulse oximeter (30,31). Baseline levels of pulse oximetry oxygen saturation (SpO 2 ) were not different in SS and control mice, as reported previously (32). After challenge with 70 μmol/kg hemin, SpO 2 in SS mice decreased progressively, reaching approximately 85% for the majority within 30 minutes (Figure 2A).…”

Platelet bioenergetic screen in sickle cell patients reveals mitochondrial complex V inhibition, which contributes to platelet activation

“…21,36 Further, mitochondrial H 2 O 2 mediates the hypoxic stabilization of hypoxia-inducible factor 1a (HIF-1a), 37 which could contribute to the aberrant normoxic stabilization of HIF-1a, which has been reported in SCD and is implicated in the pathogenesis of vasculopathy. [38][39][40] Hemolysis and platelet activation are known to be closely associated in SCD patients. 14,15,29 The current study confirms this relationship and extends it to include mitochondrial dysfunction as a mechanistic link.…”