Abstract 14565: Multidrug Resistance Associated Protein-1 (MRP-1) Deficiency Diminishes Aging Induced Cardiovascular Dysfunction
Aging induced cardiovascular dysfunction is associated with increased reactive oxygen production and inflammation. The multidrug resistance associated protein-1 (MRP-1) is the main transporter of oxidized glutathione in endothelial cells, and blockade of MRP-1 prevents endothelial cell dysfunction induced by reactive oxygen species. We therefore hypothesized that MRP-1 could play a role in cardiovascular aging. Young MRP-1-/--mice and corresponding FVB-wildtype animals at 3 month of age were compared with senescent 24 months old animals. Compared to young FVB-mice, senescent FVB-mice showed a significantly diminished acetylcholine-evoked endothelium-dependent vasorelaxation in PGF2α-precontracted thoracic aorta (pD2 7.8±0.08 vs. 8.3±0.08, p≤0.05). Senescent MRP-1-/--mice, however had an endothelium-dependent relaxation which was significantly better opposed to senescent FVB animals (pD2 8.2±0.16). The endothelium-independent relaxation induced by DEA-NONOate was not different among the groups. Vascular superoxide anion-production (measured by DHE-HPLC) was higher in senescent FVB-animals compared to senescent MRP1-deficient animals. Aortic glutathione levels were significantly higher in young MRP-1-/--mice than in FVB-mice, aging had no influence on aortic glutathione level in FVB-mice and in senescent MRP-1-/--mice aortic glutathione levels were still significantly higher. Left ventricular ejection fraction was significantly reduced in senescent FVB-wildtype animals but not in senescent MRP-1-/--mice, Also left ventricular contractility was reduced in senescent versus young FVB-mice (dP/dtmax, 4541±317 vs. 7947 ± 480 mmHg/s p≤0.01), but in aged MRP-1-/--mice preserved (6300±612 vs. 7521±421 mmHg/s n.s.). Further the diastolic function in senescent MRP1-/--mice was significantly better than in aged wildtype animals. Hearts form juvenile FVB and MRP-1-/--mice had equal amount of collagen, however in senescent hearts the amount of collagen was increased in FVB animals, but not in MRP-1-/--mice. Deficiency of MRP-1 seems to protect against aging induced vascular and cardiac dysfunction. These data indicate a yet unknown role for MRP-1 in cardiovascular aging process.
- © 2012 by American Heart Association, Inc.