| | Category | ME | L14 | High Cholesterol Impairs Water and Gas Transport in Red Blood Cells |
| | Abstract | High blood cholesterol is a major health problem, resulting in more than half |
| | a million deaths in the United States alone. It is well established that high |
| | levels of plasma cholesterol are causal to numerous diseases, including |
| | angina, diabetes, and cardiovascular disorders such as the development |
| | of arterial plaque, as a consequence of the long-term effects of high blood |
| | cholesterol. The most abundant molecule in a living cell is water (roughly |
| | 70%), which is critical to numerous life processes. Therefore, the precise |
| | and regulated transport and distribution of water in various cellular |
| | compartments is vital to life. Water can be transported slowly through |
| | biological membranes via an osmotic gradient, or rapidly transported |
| | through water channels called aquaporins (AQP). AQP1 was the first |
| | water channel to be discovered, and was first found in the red blood cell |
| | (RBC) membrane. Recent studies demonstrate the involvement of AQP1 in |
| | the transport of CO2 as well as water through the RBC membrane. |
| | Reports further demonstrate the inverse relationship of membrane |
| | cholesterol on O2 transport in RBC. In view of this, the immediate |
| | detrimental role of cholesterol on active water transport, and very likely on |
| | the CO2 and O2 transport in RBC was hypothesized, and tested in the |
| | present study. These studies were performed using isolated rat RBC, and |
| | real-time changes in RBC volume were determined using dynamic light |
| | scattering, following exposure to cholesterol and modulators of the water |
| | channel. Results from the study demonstrate that exposure of RBC to |
| | cholesterol is inhibitory to active water transport via AQP1 in the cell. In |
| | contrast, the removal of cholesterol from RBC membrane using methyl- |
| | β-cyclodextrin potentiates water transport. Recent studies suggest |
| | an increase in PLA2 activity in macrophages of coronary lesions prone to |
| | rupture, and high PLA2 activity in response to osmotic pressure in |
| | cholesterol-containing vesicles. In view of this, the role of PLA2 in RBC |
| | water transport was investigated. Surprisingly, the PLA2 inhibitor ONO- |
| | RS-082 was able to reverse cholesterol’s inhibitory effect on water |
| | transport in RBC, suggesting its potential use in the treatment of |
| | complications resulting from elevated blood cholesterol levels. The present |
| | study demonstrates for the first time the immediate detrimental effects of |
| | cholesterol on RBC function, as well as its amelioration following ONO-RS- |
| | 082 treatment. Results from this work are a major advancement in our |
| | understanding and treatment of the immediate detrimental effects of high |
| | cholesterol that likely precede angina, diabetes, and cardiovascular |
| | disorders. |
| | Bibliography | 4. G.J. Cooper, W.F. Boron. Effect of pCMBS on CO2 permeability of |
| | Xenopus oocytes expressing aquaporin 1 or its C189S mutant. Am. J. |
| | Physiol. (1998), 275:C1481– 1486. |
| | |
| | 5. E.M. Blank, H. Ehmke, H. Aquaporin-1 and HCO3-–Cl- transporter- |
| | mediated transport of CO2 across the human erythrocyte membrane. Am J |
| | Physiol (2003), 550:C419–429. |
| | |
| | 6. J.H. Steinbach, P.L. Blackshear, R.L. Varco, H. Buchwald. High blood |
| | cholesterol reduces in vitro blood oxygen delivery. J. Surg. Res. |