Acetyl-11-keto-β-boswellic acid reduces retinal angiogenesis in a mouse model of oxygen-induced retinopathy.
Retinal diseases characterized by pathologic retinal angiogenesis are the leading causes of blindness worldwide. Although therapies directed toward vascular endothelial growth factor (VEGF) represent a significant step forward in the treatment of proliferative retinopathies, further improvements are needed. In the last few years, an intense research activity has focused around the use of herbal and traditional natural medicines as an alternative for slowing down the progression of proliferative retinopathies. In the present study, we investigated the antiangiogenic effects of acetyl-11-keto-β-boswellic acid (AKBA), one of the active principles derived from the plant Boswellia serrata, used in Ayurvedic systems of medicine. We studied the antiangiogenic properties of AKBA using the mouse model of oxygen-induced retinopathy (OIR), which mimics the neovascular response seen in human retinopathy of prematurity. We first evaluated the effects of subcutaneously administered AKBA on the expression/activity of proteins which are known to play a role in the OIR model. In the retina, AKBA increased expression and activity of Src homology region 2 domain-containing phosphatase 1 and reduced the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) as well as VEGF expression and VEGF receptor (VEGFR)-2 phosphorylation. Likely as a result of these effects, AKBA significantly reduced retinal neovascularization in OIR mice without affecting retinal cell survival and retinal function. Using retinal explants cultured in hypoxia and an activator of STAT3 phosphorylation, we showed that the AKBA-induced inhibition of VEGFR-2 phosphorylation is likely to be mediated by a mechanism depending on an SHP-1/STAT3/VEGF axis. In the OIR model, neovascularization results from the activation of retinal endothelial cells, therefore we evaluated whether AKBA affected the angiogenic response of human retinal microvascular endothelial cells (HRMECs). We observed that AKBA reduced proliferation, migration and tube formation in HRMECs stimulated with exogenous VEGF, while it reduced migration and tube formation in untreated HRMECs. Taken together, our results demonstrate the antiangiogenic effects of AKBA in a model of pathologic neovascularization, providing a rationale for further investigation of AKBA as a promising therapeutic agent to reduce the impact of proliferative retinopathies.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni, 50, 50134 Florence, Italy. Electronic address: matteo.lulli@unifi.it.
Matteo
M
Lulli
Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy. Electronic address: maurizio.cammalleri@unipi.it.
Maurizio
M
Cammalleri
Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy. Electronic address: irenefornaciari@gmail.com.
Irene
I
Fornaciari
Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Via del Borghetto, 80, 56124 Pisa, Italy. Electronic address: giovanni.casini@unipi.it.
Giovanni
G
Casini
Department of Biology, University of Pisa, Via San Zeno, 31, 56127 Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Via del Borghetto, 80, 56124 Pisa, Italy. Electronic address: massimo.dalmonte@unipi.it.
Massimo
M
Dal Monte
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014315:Triterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; C094432:acetyl-11-ketoboswellic acid; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
CD31-Immunohistochemistry; Cytochrome c; Electroretinogram; HRMECs; SHP-1; STAT3; VEGF