Red Cells and Oxygen Sensing

By Peter Emanuel, M.D.

We have known for years that mechanisms of oxygen sensing and hypoxia drives erythropoiesis. But what is only now becoming clear, as eloquently elucidated by Dr. Bunn in the Scientific Committee on Hemoglobin/Red Cell, is the oxygen-dependent gene expression network and the ever-increasing list of genes that are up-regulated by falling intracellular oxygen tension that triggers the activation of the hypoxia-inducible transcription factor HIF. HIF-1a possesses a unique oxygen-dependent degradation domain (ODD) that critically controls protein stability. Under normoxic conditions, HIF-1a undergoes continuous proteolysis through the ubiquitin-protease pathway, which specifically targets the ODD of HIF-1a. Common cancer mutations such as are found in p53, HER2, and PTEN genes can enhance HIF expression. Additionally, HIF-1a and VEGF likely play key roles in recovery of myocardium from ischemic injury, as increased expression for both is noted following coronary artery occlusion. Dr. Prchal continued the discussion of HIF-1a and its downregulator, VHL, the von Hippel Lindau protein. Dr. Prchal and colleagues have described Chuvash polycythemia, which is a high erythropoietin, endemic polycythemia resultant due to a mutation in the VHL gene in affected kindreds. While these individuals develop peripheral vein varicosities, decreased blood pressure, increased stroke risks, they do not develop the classical von Hippel Lindau cancer syndrome. Certainly, Dr.Prchal made a convincing case that we do not yet completely understand the roles of HIF-1 and VEGF in carcinogenesis. Moving beyond HIF and oxygen sensing, Dr. Gladwin discussed nitric oxide (NO)-hemoglobin reactions in sickle cell disease pathogenesis. A compensatory role for NO in sickle cell disease vascular homeostasis is suggested by its multitude of functions including vaso-regulatory, anti-oxidant, and anti-thrombosis effects. These vasoregulatory homeostatic functions of NO scavenging are impaired during hemolysis, such as in sickle cell disease, when plasma oxyhemoglobin is released. This new model suggests that hemolysis leads to inhibition of NO bioavailability thus causing vasoconstriction, platelet activation, endothelial adhesion molecule expression, and endothelin-1 expression. Therapies which are capable of inactivating circulating hemoglobin are now being evaluated in sickle cell patients. Some of these therapeutic interventions include inhaled NO gas and infusion of sodium nitrite. And we thought hydroxyurea for sickle cell was hot stuff.