Monoamine oxidases are mediators of oxidative stress in human varicose Veins: interactions with obesity, inflammation, and angiotensin II

TL;DR

This study shows that monoamine oxidases, especially MAO-A, contribute to oxidative stress in varicose veins and are influenced by obesity and angiotensin II.

Contribution

The study identifies MAO-A as a novel mediator of oxidative stress in varicose veins, modulated by obesity and inflammation.

Findings

MAO-A and MAO-B are upregulated in varicose veins compared to healthy veins.

Obese patients with inflammation show significantly higher MAO-A expression.

Pharmacological MAO inhibition reduces oxidative stress in both non-stimulated and Ang II-stimulated veins.

Abstract

Chronic venous disease (CVD) and its clinical manifestation, the varicose veins (VVs), are characterized by progressive structural and functional alterations of the venous walls, with obesity/overweight being one of the most frequent comorbidities. Monoamine oxidases (MAO-A and MAO-B) are mitochondrial flavoenzymes responsible for the constant generation of hydrogen peroxide (H2O2) during the catabolism of biogenic monoamines and neurotransmitters that contribute, when upregulated, to the oxidative stress in most mammalian tissues. However, their role in the VV pathophysiology and its modulation by vasoactive stimuli such as angiotensin II (Ang II) remains unclear. This exploratory study was double-aimed i) to assess MAO expression in human VV samples in relation to obesity and systemic inflammation and ii) to determine the impact of pharmacological MAO inhibition on oxidative stress under basal and Ang II–stimulated conditions. To this aim, 20 patients with VV and an indication for cryostripping were randomized according to their body mass index (BMI) into obese (n = 10) and non-obese (n = 10) groups, and VV samples were harvested and used to assess the following: i) MAO-A and MAO-B gene expression by qRT-PCR, as well as expression and localization by immunofluorescence, and ii) H2O2 by means of the ferrous xylenol orange oxidation (FOX) assay. Furthermore, the effect of selective MAO inhibition (clorgyline 10 μM for MAO-A, selegiline 10 μM for MAO-B) was tested ex vivo both at baseline and following acute stimulation with Ang II (100 nM). We showed that both MAO-A and MAO-B are constitutively expressed in the human venous walls, with higher levels in the varicose veins than in the adjacent perforator veins. The obese patients with inflammatory status (elevated serum C-reactive protein) had significantly increased MAO-A (but not MAO-B) expression as compared to the non-obese controls (p < 0.01). Acute ex vivo incubation with Ang II further enhanced the expression of both isoforms and increased H2O2 generation. MAO inhibition significantly mitigated the oxidative stress in both non-stimulated and Ang II–stimulated samples, regardless of the presence or absence of obesity. In conclusion, MAO isoforms, in particular MAO-A, are upregulated in the human varicose veins and can be further induced by Ang II, especially in the setting of obesity associated with low-grade inflammation. MAO contributed to the local oxidative stress, which was significantly reduced by its pharmacological inhibition with MAO-A and B inhibitors, thus pointing to MAO as a potential therapeutic target in patients with CVD.

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