Hypercholesterolemia Enhances 15-Lipoxygenase-Mediated Vasorelaxation and Acetylcholine-Induced Hypotension

Objective - Arachidonic acid (AA) metabolites from 15-lipoxygenase-1 (15-LO-1), trihydroxyeicosatrienoic acid (THETA), and hydroxyepoxyeicosatrienoic acid (HEETA) relax arteries. We studied 15-LO-1 expression, THETA and HEETA synthesis, and their effect on arterial relaxations and blood pressure in hypercholesterolemic nonatherosclerotic rabbits. Methods and Results - Immunoblots, RTPCR analysis, and C-14-AA metabolism revealed that hypercholesterolemia increased 15-LO-1 expression in the endothelium and THETA and HEETA synthesis in the arteries. Isometric tension recording, in presence of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitors, showed greater relaxations to acetylcholine (ACH) and AA (max 76.0 +/- 4.6% and 79.5 +/- 2.4%, respectively) in aortas from hypercholesterolemic rabbits compared with normal rabbits (max 39.1 +/- 2.8% and 39.9 +/- 2.2%, respectively). AA induced greater hyperpolarization in the smooth muscle cells of hypercholesterolemic aortas (-45.85 +/- 3.0 mV) compared with normal aortas (-31.45 +/- 1.9 mV). The ACH-and AA-relaxations were inhibited by 15-LO-1 inhibitors. ACH induced hypotensive responses were greater in hypercholesterolemic rabbits in absence (-54.9 +/- 3.3%) or presence (-48.5 +/- 3.2%) of NOS and COX-inhibitors compared with control rabbits (-31.6 +/- 3.3% and -24.3 +/- 1.6%, respectively). BW755C reduced these responses in hypercholesterolemic rabbits to -29.3 +/- 2.3%. Conclusion - Hypercholesterolemia increases endothelial 15-LO-1 expression, THETA and HEETA synthesis and enhances vasorelaxation. (Arterioscler Thromb Vasc Biol. 2008; 28: 2209-2215.)