Key result
MAO inhibitors reduced lipopolysaccharide- and angiotensin II-induced aortic reactive oxygen species formation by 50% and completely restored endothelium-dependent relaxation in mouse models.
Why the study?
Do MAO inhibitors prevent endothelial dysfunction in mouse models of vascular disease?
Do MAO inhibitors prevent endothelial dysfunction in mouse models of vascular disease?
MAO-A and MAO-B contribute to endothelial dysfunction via H2O2 generation in vascular disease models, and their combined inhibition completely restores endothelium-dependent relaxation.
MAO inhibition may restore endothelial function in mouse vascular models; leaves open translation to human hypertension therapy.
Monoamine oxidases (MAOs) generate H(2)O(2) as a by-product of their catalytic cycle. Whether MAOs are mediators of endothelial dysfunction is unknown and was determined here in the angiotensin II and lipopolysaccharide-models of vascular dysfunction in mice. Quantitative real-time polymerase chain reaction revealed that mouse aortas contain enzymes involved in catecholamine generation and MAO-A and MAO-B mRNA. MAO-A and -B proteins could be detected by Western blot not only in mouse aortas but also in human umbilical vein endothelial cells. Ex vivo incubation of mouse aorta with recombinant MAO-A increased H(2)O(2) formation and induced endothelial dysfunction that was attenuated by polyethylene glycol-catalase and MAO inhibitors. In vivo lipopolysaccharide (8 mg/kg IP overnight) or angiotensin II (1 mg/kg per day, 2 weeks, minipump) treatment induced vascular MAO-A and -B expressions and resulted in attenuated endothelium-dependent relaxation of the aorta in response to acetylcholine. MAO inhibitors reduced the lipopolysaccharide- and angiotensin II-induced aortic reactive oxygen species formation by 50% (ferrous oxidation xylenol orange assay) and partially normalized endothelium-dependent relaxation. MAO-A and MAO-B inhibitors had an additive effect; combined application completely restored endothelium-dependent relaxation. To determine how MAO-dependent H(2)O(2) formation induces endothelial dysfunction, cyclic GMP was measured. Histamine stimulation of human umbilical vein endothelial cells to activate endothelial NO synthase resulted in an increase in cyclic GMP, which was almost abrogated by MAO-A exposure. MAO inhibition prevented this effect, suggesting that MAO-induced H(2)O(2) formation is sufficient to attenuate endothelial NO release. Thus, MAO-A and MAO-B are both expressed in the mouse aorta, induced by in vivo lipopolysaccharide and angiotensin II treatment and contribute via the generation of H(2)O(2) to endothelial dysfunction in vascular disease models.
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Sturza et al. (2013) studied Endothelial dysfunction. MAO inhibitors was evaluated on Aortic reactive oxygen species formation and endothelium-dependent relaxation. MAO inhibitors reduced lipopolysaccharide- and angiotensin II-induced aortic reactive oxygen species formation by 50% and completely restored endothelium-dependent relaxation in mouse models.
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