The immunosuppressive macrolide tacrolimus (FK-506) is used clinically to reduce allograft rejection; however, long-term administration leads to endothelial cell dysfunction and hypertension through activation of conventional protein kinase C (cPKC) and inhibition of endothelial nitric-oxide synthase (eNOS). The study by Chiasson et al. was aimed at determining the cPKC isoform that is activated by tacrolimus and that leads to decreased endothelial cell function. Tacrolimus induced the inactivating phosphorylation of eNOS on Thr495 independently of tacrolimus/FK-506 binding protein-12–mediated inhibition of calcineurin. By using an isoform-specific peptide inhibitor of PKC βII, the endothelium-dependent relaxation response in aortas could be restored after tacrolimus treatment, suggesting that PKC βII is involved in the functional response to tacrolimus. The peptide inhibitor was also shown to prevent the tacrolimus-induced phosphorylation of eNOS at Thr 495. These results suggest that, once activated, PKC βII phosphorylated eNOS at its inhibitory site Thr495, leading to a decrease in endothelial function that could contribute to the hypertension observed with long-term tacrolimus administration. Inhibition of PKC βII could prove beneficial in treating hypertension induced by long-term administration of tacrolimus as well as rectifying endothelial cell dysfunction induced by β amyloid peptide or hyperhomocystinemia.
See article at J Pharmacol Exp Ther 2011, 337:718–723
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics