Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and... Show moreMonoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAHand in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV Show less
Alpha-1 antitrypsin (AAT) acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered as the primary source of AAT, local production by monocytes,... Show moreAlpha-1 antitrypsin (AAT) acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered as the primary source of AAT, local production by monocytes, macrophages and epithelial cells may contribute to the formation of an anti-elastase screen. Since monocytes can differentiate into a heterogeneous population of macrophages with subpopulations ranging from pro-inflammatory properties (MΦ-1) to anti-inflammatory properties (MΦ-2) and into dendritic cells (DC), we studied whether lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) and oncostatin M (OSM) enhance AAT production differentially in cultured MΦ-1, MΦ-2 and DC. Monocytes from healthy blood donors were cultured for 7 days in the presence of GM-CSF, M-CSF, or GM-CSF and IL-4 to obtain MΦ-1, MΦ-2 and immature(i)DC, respectively. Next, cells were stimulated with LPS, TNFα or OSM and synthesis of AAT was assessed by quantitative RT-PCR, immunocytochemistry and ELISA. Spontaneous release of AAT was higher in MΦ-1 than in MΦ-2 and iDC and only LPS significantly increased AAT production in MΦ-1, MΦ-2 and DC, whereas TNFα and OSM did not affect AAT secretion. The secretion levels of the related protease inhibitors alpha-1 antichymotrypsin (ACT) and secretory leucocyte proteinase inhibitor (SLPI) were below the limits of detection by ELISA. In contrast to the protein data, analysis by quantitative RT-PCR showed that 24h LPS exposure caused a maximal 2.1-fold AAT mRNA increase in MΦ-1, a 21-fold increase in MΦ-2 and 11-fold increase in DC. These data suggest that cellular differentiation is a regulator of local AAT production. Show less
