| First Author | Kaul DK | Year | 2013 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 304 |
| Issue | 1 | Pages | H42-50 |
| PubMed ID | 23125209 | Mgi Jnum | J:192836 |
| Mgi Id | MGI:5466636 | Doi | 10.1152/ajpheart.00296.2012 |
| Citation | Kaul DK, et al. (2013) Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1alpha expression in normoxic sickle mice: microvascular implications. Am J Physiol Heart Circ Physiol 304(1):H42-50 |
| abstractText | 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-1alpha (HIF-1alpha) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1alpha, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1alpha in normoxic BERK mice expressing exclusively human alpha- and beta(S)- globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., <1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1alpha 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-1alpha 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-1alpha 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-1alpha, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1alpha activation. Thus HIF-1alpha 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. |
