High cholesterol impairs water and gas transport in red blood cells and is ameliorated by the PLA2 inhibitor ONO-RS-082

Abstract

Elevated levels of plasma cholesterol pose significant health risks and are causal to diseases including angina, cardiovascular disorders and diabetes. Although the long-term effect of elevated plasma cholesterol is known for its accretion in arterial walls, little is understood of its immediate effects. Since cholesterol levels in red blood cell (RBC) membranes are inversely associated with O 2 transport, and the RBC water channel AQP1 is also capable of transporting CO 2 , the detrimental effect of cholesterol on active water transport, and likely on the CO 2 and O 2 transport in RBC, was hypothesized and tested in the present study. The rapid gating of water into isolated rat RBC and the corresponding increase in their volume and surface area was determined using dynamic light scattering. Similarly, the entry of CO 2 into the RBC was determined using zeta potential measurements, as increase in intracellular acidity reduces the negative charge at the RBC membrane. Results from our study demonstrate for the first time that the immediate effect of elevated plasma cholesterol is dysfunction of active water and CO 2 transport, possibly via the AQP1 channel at the RBC membrane. Since there is growing evidence that PLA2 may play a key role in atherogenesis, and statins significantly reduce blood PLA2 levels, the effect of the PLA2 inhibitor on ameliorating the detrimental effects of cholesterol was investigated. Interestingly, the PLA2 inhibitor ONO-RS-082 was found to reverse the cholesterol effect on RBC function.