<p>Low-dose doxycycline inhibits hydrogen peroxide-induced oxidative stress, MMP-2 up-regulation and contractile dysfunction in human saphenous vein grafts</p>

Abstract

Background: Cardiopulmonary bypass (CPB) applied during coronary artery bypass grafting (CABG), promotes inflammation, generation of reactive oxygen species (ROS) and up-regulation of matrix metalloproteinases (MMPs). All these complications may lead to contractile dysfunction, restenosis and early graft failure, restricting long-term efficacy of bypass grafts. Low-dose doxycycline is a potent MMP inhibitor and ROS scavenger. In this study, we aimed to investigate the effects of doxycycline on ROS generation, MMP regulation and contractile dysfunction induced by H 2 O 2 in human saphenous vein (HSV) grafts. Methods: HSV grafts (n=7) were divided into four groups after removing endothelial layer by mechanical scratching and incubated with 10 µM H 2 O 2 and/or 10 µM doxycycline for 16 hrs. Untreated segments served as control. Concentration–response curves to noradrenaline (NA), potassium chloride (KCl), serotonin (5-HT) and papaverine were performed. Superoxide anion and other ROS levels were determined by using lucigenin- and luminol-enhanced chemiluminescence assays, respectively. Expression/activity of gelatinases (MMP-2/MMP-9) was examined by gelatin zymography. MMP-13 expression was evaluated by immunostaining/immunoscoring. Results: H 2 O 2 incubation increased superoxide anion and other ROS levels. Doxycycline prevented these increments. H 2 O 2 suppressed contractile responses to NA, KCl and 5-HT. Doxycycline ameliorated contractions to NA and KCl but not to 5-HT. H 2 O 2 or doxycycline did not altered relaxation to papaverine. MMP-2 and MMP-13 expression increased with H 2 O 2 , but doxycycline inhibited MMP-2 up-regulation/activation. Conclusion: Low-dose doxycycline may have beneficial effects on increased oxidative stress, MMP up-regulation/activation and contractile dysfunction in HSV grafts.

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

“…Along these lines, the reversal of CS-induced emphysema and PH by riociguat treatment in mice was associated with decreased MMP activity and expression (4). It has been shown that doxycycline not only inhibited MMP activity but also decreased MMP expression (27,31,50). In our current study, doxycycline decreased MMP-2 and MMP-9 expression on the protein level in the lung homogenates from mice that were exposed to CS.…”

Application of Oxidative Stress to a Tissue-Engineered Vascular Aging Model Induces Endothelial Cell Senescence and Activation

“…Treatment with 100 µM H 2 O 2 did not affect vasoconstriction in response to 1 µM phenylephrine in the TEBVs (Figure 3A,C). In contrast, human saphenous vein samples showed a reduction in vasoconstriction ex vivo when treated with as little as 10 µM H 2 O 2 for 16 h [32]. It is important to note that these data were obtained using a much higher concentration of noradrenaline (100 µM) as a vasoconstrictor, rather than the low dose of phenylephrine (1 µM) used here.…”

Failure Analysis of TEVG’s II: Late Failure and Entering the Regeneration Pathway

“…Other reports demonstrated that high wall-shear stress and cyclic shear stress increase the expression of Angiopoietin-2 and its receptor Tie2, which leads to activation of the PI3K/Akt pathway. This results in the expression of eNOS and the subsequent increase in the released NO from ECs [87,88].…”