Lipoxin A₄ mediates aortic contraction via rhoa/rho kinase, endothelial dysfunction and reactive oxygen species

Background: Lipoxin A4 (LXA₄) is a biologically active product generated from arachidonic acid by lipoxygenase action. The production of lipoxins is enhanced by aspirin through acetylation of cyclooxygenase-2, via a mechanism known as 'aspirin-triggered lipoxin'. LXA₄ has both anti-inflammatory and proinflammatory actions, the latter being related with reocclusion and restenosis after coronary angioplasty in patients treated with aspirin. However, little is known of the actions of LXA₄ on the vasculature. We hypothesized that LXA₄ promotes contractile responses and contributes to endothelial dysfunction. Methods: We used aorta from Wistar rats to assess vascular function. Reactive oxygen species (ROS) production and contractile and regulatory proteins were investigated. Results: LXA₄ induced concentration-dependent contractions via formyl peptide receptor-2 activation and both RhoA/Rho kinase inhibitor and ROS scavenger decreased this contraction. Also, endothelium removal, and COX-2 and NAD(P)H oxidase inhibitors attenuate the LXA₄-induced contraction. LXA₄ potentiated phenylephrine-induced contraction and inhibited acetylcholine-induced relaxation. In the presence of LXA₄, ROS production was increased and protein expression of RhoA, phospho-myosin light chain, COX-2 and p67phox was higher. Conclusion: LXA₄ has a functional role in the vasculature and may contribute to further vascular damage in conditions where its production is exacerbated, such as in angioplasty-associated complications treated with aspirin.