Andrographolide suppresses cisplatin-induced endothelial hyperpermeability through activation of PI3K/Akt and eNOS -derived nitric oxide.

Cisplatin upregulate the intercellular adhesion molecule expression on the surface of endothelium, which in turn mediates enhanced infiltration by monocytes or leukocytes, resulting in endothelial dysfunction. Here we examined changes induced by andrographolide, a diterpenoid lactone isolated from Andrographis paniculata on endothelial cell activation and hyperpermeability in cisplatin-stimulated endothelial cells. Cisplatin upregulated endothelial ICAM-1 expression, through an NF-κB dependent mechanism, that also required the enhanced translocation of Protein Kinase C-α (PKC) onto the plasma membrane, phosphorylation of transient receptor potential channel 1 (TRPC), leading to store-operated Ca2+-entry (SOCE), endothelial cell dysfunction and hyperadhesion of U937 monocytes. Pretreatment of endothelial cells with andrographolide prior to stimulation with cisplatin resulted in activation of PI3K/Akt and eNOS, production of nitric oxide (NO) and cGMP, with a consequential lowering of endothelial cell leakiness and improved transendothelial electrical resistance. Andrographolide-induced NO was essential for NF-κB inhibition, lowered ICAM-1 expression as well as prevention of SOCE and reduced the U937 binding to cisplatin-stimulated endothelial cells.