CC-PLA2-1 and CC-PLA2-2, two Cerastes cerastes venom-derived phospholipases A2, inhibit angiogenesis both in vitro and in vivo.
Integrins are essential in the complex multistep process of angiogenesis and are thus attractive targets for the development of antiangiogenic therapies. Integrins are antagonized by disintegrins and C-type lectin-like proteins, two protein families from snake venom. Here, we report that CC-PLA2-1 and CC-PLA2-2, two novel secreted phospholipases A(2) (PLA(2)) isolated from Cerastes cerastes venom, also showed anti-integrin activity. Indeed, both PLA(2)s efficiently inhibited human brain microvascular endothelial cell adhesion and migration to fibrinogen and fibronectin in a dose-dependent manner. Interestingly, we show that this anti-adhesive effect was mediated by alpha5beta1 and alphav-containing integrins. CC-PLA2s also impaired in vitro human brain microvascular endothelial cell tubulogenesis on Matrigel and showed antiangiogenic activity in vivo in chicken chorioallantoic membrane assay. The complete PLA(2) cDNAs were cloned from a venom gland cDNA library. Mature CC-PLA2-1 and CC-PLA2-2 contain 121 and 120 amino acids, respectively, including 14 cysteines each and showed 83% identity. Tertiary model structures of CC-PLA2-1 and CC-PLA2-2 were generated by homology modeling. This is thus the first study describing an antiangiogenic effect for snake venom PLA(2)s and reporting first clues to their mechanism of action on endothelial cells.
Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, Tunis, Tunisia.
Raoudha
R
Kessentini-Zouari
Jed
J
Jebali
Salma
S
Taboubi
Najet
N
Srairi-Abid
Maram
M
Morjen
Olfa
O
Kallech-Ziri
Sofiane
S
Bezzine
Jacques
J
Marvaldi
Mohamed
M
El Ayeb
Naziha
N
Marrakchi
José
J
Luis
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D049033:Chorioallantoic Membrane / Q000187:drug effects; D042783:Endothelial Cells; D022001:Focal Adhesions / Q000187:drug effects; D054498:Group I Phospholipases A2 / Q000737:chemistry / Q000494:pharmacology*; D054501:Group II Phospholipases A2 / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000187:drug effects*; D008961:Models, Structural; D055672:Static Electricity; D014757:Viper Venoms / Q000737:chemistry / Q000201:enzymology*
D020533:Angiogenesis Inhibitors; D016023:Integrins; D014757:Viper Venoms; D054498:Group I Phospholipases A2; D054501:Group II Phospholipases A2