Abstract
Background and PurposeFK506 and rapamycin are modulators of FK‐binding proteins (FKBP) that are used to suppress immune function after organ and hematopoietic stem cell transplantations. The drugs share the unwanted side‐effect of evoking hypertension that is associated with reduced endothelial function and nitric oxide production. The underlying mechanisms are not understood. FKBP may regulate IP3 receptors (IP3R) and ryanodine receptors (RyR) to alter Ca2+ signalling in endothelial cells.Experimental ApproachWe investigated the effects of FK506 and rapamycin on Ca2+ release via IP3R and RyR in hundreds of endothelial cells, using the indicator Cal‐520, in intact mesenteric arteries from male Sprague‐Dawley rats. IP3Rs were activated by acetylcholine or localised photo‐uncaging of IP3, and RyR by caffeine.Key ResultsWhile FKBPs were present, FKBP modulation with rapamycin did not alter IP3‐evoked Ca2+ release. Conversely, FK506, which modulates FKBP and blocks calcineurin, increased IP3‐evoked Ca2+ release. Inhibition of calcineurin (okadiac acid or cypermethrin) also increased IP3‐evoked Ca2+ release and blocked FK506 effects. When calcineurin was inhibited, FK506 reduced IP3‐evoked Ca2+ release. These findings suggest that IP3‐evoked Ca2+ release is not modulated by FKBP, but by FK506‐mediated calcineurin inhibition. The RyR modulators caffeine and ryanodine failed to alter Ca2+ signalling suggesting that RyR is not functional in native endothelium.Conclusion and ImplicationsThe hypertensive effects of the immunosuppressant drugs FK506 and rapamycin, while mediated by endothelial cells, do not appear to be exerted at the documented cellular targets of Ca2+ release and altered FKBP binding to IP3 and RyR.
Highlights
These results suggest that the increase in inositol 1 (IP3)-evoked Ca2+ release generated by FK506 is mediated by an effect of the drug on calcineurin rather than FK-binding proteins (FKBPs) modulation itself
While immunosuppressant-induced hypertension coupled with endothelial dysfunction is significant in the systemic circulation, this may not be the case in the pulmonary circulation
In native endothelial cells on intact blood vessels, we explored the possibility that FKBP binding to IP3 receptors (IP3R) and ryanodine receptors (RyR) may regulate Ca2+ signalling and contribute to the effects of the immunosuppressants on vascular function
Summary
Reduced endothelium-dependent relaxation was reported in mouse aorta after FK506 treatment (Chiasson et al, 2011; Cook, Chiasson, Long, Wu, & Mitchell, 2009) These findings raise the possibility that IP3R and RyR may contribute to the altered endothelial function induced by the immunosuppressant drugs. Calcineurin activity failed to alter Ca2+ in cultured aortic endothelial cells (Cook et al, 2009) Together, these studies highlight a confused picture of the regulation of endothelial Ca2+ signalling by FKBP and its disruption via the immunosuppressant drugs FK506 and rapamycin.
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