Presenilin inhibition increases intracellular calcium stores via a decrease in sarcoplasmic reticulum calcium leakage

Calcium dysregulation is a known variable in the vascular pathology of hypertension. Most recently, an extensively studied group of molecules are the presenilins (PS). Although many studies using different cell lines emphasize the role of presenilin in calcium regulation, this area is controversial and the mechanisms are still not well understood. Our study determines the role of presenilins in the vasculature, using an ex vivo model. We hypothesize that inhibition of presenilin increases calcium uptake by intracellular stores leading to exaggerated calcium response. Using DAPT (50uM) a secretase inhibitor that binds and inhibits presenilins, we observed an increase in caffeine mediated contraction compared to vehicle in the presence or the absence of a SERCA inhibitor. We also observed an increased phenylephrine-mediated contraction after intracellular store depletion, showing that the resting level of calcium inside SR is increased with PS inhibition. Recent publications have shown that PS increase intracellular calcium by either forming a novel leak channel in SR or by increasing the leak of calcium through other “SR leak channels” .Our data support these findings and provide a better insight to the role of presenilins in calcium homeostasis in vascular smooth muscle cells.