MnTBAP increases BMPR-II expression in endothelial cells and attenuates vascular inflammation

Abstract

Aims The endothelium plays an important role during vascular inflammation. Previous data have demonstrated a high expression level of manganese-superoxide dismutase (MnSOD) in endothelial cells and suggested an important role of MnSOD in several cardiovascular diseases. Manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) has been shown to mimic some of the effects of MnSOD and prevented the development of diabetes and obesity. However, its effect on vascular inflammation and the underlying mechanism is still unknown. Methods and results Leukocyte adhesion was evaluated in-vivo and in-vitro using dynamic flow chamber and intravital microscopy in mice. Expression of adhesion molecules induced by TNFα and adhesion of leukocytes to the vessel wall were inhibited by MnTBAP. The anti-inflammatory effect of MnTBAP was partly mediated by up-regulation of the BMPR-II and Smad dependent pathway. Additionally, MnTBAP decelerated the turn-over of endogenous BMPR-II. Conclusion Our data demonstrate that MnTBAP activates Smad signaling, preserves the turn-over of BMPR-II and elicits anti-inflammatory effects in endothelial cells, partly mediated by BMPR-II. This finding suggests a potential therapeutic impact of MnTBAP in the treatment of vascular inflammation.

MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension

“…We have shown that even in the presence of CHX, MnTBAP increases BMPR2 levels in PAECs. This goes in line with our previous findings, where pre-treatment of HUVECs with MnTBAP for 16 h prior to addition of CHX increased BMPR2 stability [25]. In summary, our data suggest that MnTBAP modulates BMPR2 degradation and underlines the role of such compound as a favorable PAH treatment.…”

“…As expected, BMPR2 levels were significantly increased after BafA1 treatment [12] ( Figure 1A). Consistent with our previous findings [25], MnTBAP treatment resulted in a dose-depndent increase of BMPR2 protein levels in PAECs ( Figure 1A or B). No significant differences on BMPR2 mRNA levels were observed after MnTBAP treatment, indicating no changes at the transcriptional level ( Figure 1C).…”

“…Rescuing BMPR2 expression, function or signaling represents a promising treatment for PAH patients [18][19][20]. Manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a synthetic metalloporphyrin with antioxidant [21][22][23] and anti-inflammatory [23][24][25][26] effects, has been shown to inhibit the turn-over of BMPR2 in human umbilical vein endothelial cells (HUVECs) [25]. Moreover, MnTBAP offers beneficial effects in bleomycin-induced pulmonary fibrosis [27], carrageenan-induced pleurisy [28], lung contusion [26], renal fibrosis [29] and renal injury [24,30].…”

The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions

“…Several studies indicated that Mn supplementation could reduce high glucose-induced monocyte adhesion to endothelial cells and endothelial dysfunction and also lower blood levels of ICAM-1 and cholesterol [ 48 , 49 ], elicit anti-inflammatory effects in endothelial cells [ 100 ], and potentially prevent or delay the progression of atherosclerosis. Little is known about the Mn concentration in atherosclerosis patient samples.…”

Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate

“…6 and 7). While a fair amount of data exist on the ability of MnTBAP 3to reduce normal tissue injuries (9,12,53,61,64), this MnP may not have the potential as an anticancer therapeutic.…”