| Popis: |
12/15-LO (12/15-Lipoxygenase), encoded by Alox15 gene, metabolizes arachidonic acid to 12(S)-HETE (12-hydroxyeicosatetraenoic acid). Macrophages are the major source of 12/15-LO among immune cells, and 12/15-LO plays a crucial role in development of hypertension. Global Alox15- or macrophage-deficient mice are resistant to AngII (angiotensin II)-induced hypertension. This study tests the hypothesis that macrophage 12(S)-HETE contributes to AngII-mediated arterial constriction and thus to development of AngII-induced hypertension. AngII constricted isolated abdominal aortic and mesenteric arterial rings. 12(S)-HETE (100 nM) alone was without effect; however, it significantly enhanced AngII-induced constriction. The presence of wild type macrophages also enhanced the AngII-induced constriction, while Alox15(−/−) macrophages did not. Using this model, pre-treatment of aortic rings with inhibitors, receptor agonists/antagonists, or removal of the endothelium, systematically uncovered an endothelium-, AngII receptor-2- and superoxide-mediated enhancing effect of 12(S)-HETE on AngII constrictions. The role of superoxide was confirmed using aortas from p47(phox−/−) mice where 12(S)-HETE failed to enhance constriction to AngII. In cultured arterial endothelial cells, 12(S)-HETE increased the production of superoxide, and 12(S)-HETE and/or AngII increased the production of an isothromboxane-like metabolite. A TP (thromboxane receptor) antagonist inhibited 12(S)-HETE enhancement of AngII constriction. Both AngII-induced hypertension and the enhancing effect of 12(S)-HETE on AngII contractions were eliminated by a BLT2 (leukotriene B(4) receptor-2) antagonist. These results outline a mechanism where the macrophage-12/15-LO pathway enhances the action of AngII. 12(S)-HETE, acting on the BLT2, contributes to the hypertensive action of AngII in part by promoting endothelial synthesis of a superoxide-derived TP agonist. |
