Abstract 16226: Cytoglobin Effectively Regulates the Oxygen-Dependent Consumption of Nitric Oxide in the Vascular Wall
Nitric oxide (NO), an endogenous vasodilator, is consumed in the vascular wall in an oxygen-dependent manner. It has been documented that the oxygen-dependent NO consumption can act as an oxygen sensor to change NO diffusion distance for regulating vascular tone; however, the detailed molecular mechanism was unknown. Recent evidence showed that cytoglobin (Cygb) is expressed in the vascular wall and can mediate oxygen-dependent NO consumption. To test if Cygb is a strong candidate for acting as an oxygen sensor, we used electrochemical and UV/Vis spectroscopic techniques combined with mathematical models to examine the interaction between Cygb, NO, oxygen and a cellular reductant (ascorbate), and compared results with Mb. It was observed that the rate of NO consumption by either Cygb (0.3 μM) or Mb (0.3 μM) at 37 °C in the presence of 300 μM ascorbate gradually decreased as oxygen concentration decreased; however, in the range of low PO2 (0–40 mmHg), the rate change of NO consumption by Cygb is 3 times greater than that by Mb in the same range of PO2, indicating that Cygb is much more efficient in regulating NO consumption rate under hypoxic conditions. Further experiments showed that the rate of NO consumption by Cygb in the presence of ascorbate is 2–3 times greater than by Mb at higher PO2 (>40 mmHg). Correspondingly, the rate of Cygb reduction by ascorbate (100 μM-10 mM) is at least several-fold greater than the rate of Mb reduction by ascorbate (100 μM-10 mM). At low PO2 (7.5 mmHg), a prior addition of 3 μM NO into the solution containing 0.3 μM Cygb and 300 μM ascorbate reduced the decay rate of NO in the following additions by more than 40%. In contrast, there were no appreciable changes in the rate of NO decay by Mb under the same experimental conditions. A mathematical model was developed to simulate the effect of O2, ascorbate, and NO itself on the Cygb-mediated NO consumption. The simulation results showed that the increased rate of Cygb reduction by ascorbate is beneficial for increasing the Cygb-mediated NO consumption at higher PO2, while the significant NO binding to Cygb at lower PO2 greatly reduces the Cygb-mediated NO consumption in hypoxia. In this way, Cygb, acting as an oxygen sensor, effectively regulates NO consumption rate in response to oxygen changes.
- © 2010 by American Heart Association, Inc.