Repressed Ca2+ clearance in parthenolide-treated murine brain bEND.3 endothelial cells

Abstract Parthenolide is a sesquiterpene lactone compound isolated from the leaves and flowerheads of the plant feverfew ( Tanacetum parthenium) . The anticancer effects of parthenolide have been well studied and this lactone compound is currently under clinical trials. Parthenolide is also a protective agent in cardiac reperfusion injury via its inhibition of nuclear factor-κB (NF-κB). Not much is known if this compound affects signal transduction in non-tumor cells. We investigated whether parthenolide affected Ca 2+ signaling in endothelial cells, key components in regulating the vascular tone. In this work using mouse cortical microvascular bEND.3 endothelial cells, we found that a 15-h treatment with parthenolide resulted in amplified ATP-triggered Ca 2+ signal; the latter had a very slow decay rate suggesting suppression of Ca 2+ clearance. Evidence suggests parthenolide suppressed Ca 2+ clearance by inhibiting the plasmalemmal Ca 2+ pump; such suppression did not result from decreased expression of the plasmalemmal Ca 2+ pump protein. Rather, such suppression was possibly a consequence of endoplasmic reticulum (ER) stress, since salubrinal (an ER stress protector) was able to alleviate parthenolide-induced Ca 2+ clearance suppression. Given the current deployment of parthenolide as an anti-cancer drug in clinical trials and the potential usage of this lactone as a cardioprotectant, it is important to examine in details the perturbing effects of parthenolide on Ca 2+ homeostasis in endothelial cells and neighboring vascular smooth muscle cells, activities of which exert profound effects on hemodynamics.