Monoamine Oxidases Are Mediators of Endothelial Dysfunction in the Mouse Aorta

Abstract

Abstract-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 lipopolysaccharidemodels 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. Sturza et al MAOs in Endothelial Dysfunction 141MAO-A-mediated H 2 O 2 production has been shown to be relevant for ischemia-reperfusion injury of the kidney 11 and the heart. Moreover, MAO-A is thought to be involved in myocyte hypertrophy ex vivo 12,13 and also in maladaptive myocardial hypertrophy and transition to heart failure in vivo.14 The unfavorable effects of MAO activation are antagonized by a couple of relatively selective MAO inhibitors, which are either irreversible, such as clorgyline for MAO-A and selegiline for MAO-B, or reversible, such as moclobemide for MAO-A and lazabemide for MAO-B, respectively.8 Systemic MAO inhibition leads to the accumulation of catecholamines with subsequent increase in sympathetic activity and hypertension. 15 This aspect limits the use of MAO inhibitors in a vascular scenario, and therefore, MAO inhibitors have not been considered an approach to improve vascular function.Another prototypic hypertensive agent is angiotensin II (Ang II). Interestingly, potential interactions of Ang II and MAOs have been reported in the central nervous system. In coculture systems of hypothalamic and brain stem neurons, Ang II stimulated MAO activity, but the underlying mechanism was not studied. 16 More recently, it was reported that in...

Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes

“…Quantitative RT-PCR was performed as previously described (Sturza et al 2013a). Primers against MAO isoforms were designed using the sequence information (5=-3=) for rat from the NCBI database.…”

Redox-mediated signal transduction by cardiovascular Nox NADPH oxidases

“…For oxidation, "redox-generators" are required and cells harbor enzymes directly capable of protein oxidation, like the endoplasmic reticulum oxidase ERO-1. Also ROS are important mediators of protein oxidation and are generated as reactive byproducts in mitochondria, by cytochrome P450 monooxygenases or by monoamine oxidase [4] and others. Interestingly, with the Nox family of NADPH oxidases, an enzyme system, the only known function of which is ROS production, has evolved [5].…”

Monoamine oxidase inhibition improves vascular function in mammary arteries from nondiabetic and diabetic patients with coronary heart disease

“…However, we speculate that a decrease in nitric oxide (NO) availability is the underlying mechanism. Indeed, we have previously reported in HUVECs that MAO-A directly limits the accumulation of cGMP and thus, NO formation (Sturza et al 2013). However, other pleiotropic effects of MAOI cannot be excluded.…”

“…Recently, we described the role of MAOs as mediators of endothelial dysfunction and the beneficial effect of MAO inhibition in murine diseased vessels (Sturza et al 2013), and in experimental diabetes mellitus, respectively (Duicu et al 2015;Sturza et al 2015). …”

“…Hypertension is a risk factor clearly involved in the maintenance of chronic inflammation and progression of atherosclerotic lesions (Rosendorff et al 2015). In experimental settings, we have previously reported that acute administration of lipopolysaccharide (with subsequent inflammation) or chronic delivery of angiotensin II (with subsequent hypertension) lead to overexpression of both MAO isoforms, increase in ROS production and impairment of vascular relaxation (Sturza et al 2013). Second, medication can also modify the enzyme expression.…”