Dysregulation of capacitative calcium entry in hypertensive rats associated to mitochondrial dysfunction

Abstract

Mitochondria located in close proximity to high Ca2+ microdomains are able to buffer it. We hypothesized that this process is impaired in vascular cells inducing adaptive changes, which affect capacitative calcium entry (CCE) and develop a cytosolic calcium overload in spontaneously hypertensive rats (SHR). This conclusion is supported by the following findings in SHR, compared with normotensive Wistar Kyoto rats: 1) augmented contraction of vascular tone by depletion of intracellular Ca2+ stores with caffeine, ryanodine or thapsigargin in 0 Ca2+ solutions; 2) the reintroduction of 2.5 Ca2+ induced higher contractions; 3) these contractions were antagonized by Gd3+, La3+ and SKF-96365 (a STIM-1 inhibitor); 4) similar results were obtained in smooth muscular cells (SMC) cultures by fluorescence; 5) western-blot and immunofluorescence shows STIM-1 expression up-regulation both in aorta tissue and SMC; 6) aortic contractility is impaired before FCCP incubation. These results support the hypothesis that mitochondrial dysfunction affect the CCE, an important factor in the calcium overload and cell damage. The cytosolic Ca2+ overload in SHR due to the mitochondrial failure perform a negative feedback in the store operated channel preventing the Ca2+ entry. The suppression of this Ca2+ influx is balanced with a STIM-1 overexpression, leading to a greater CCE when reticulum depletion occurs. Thus, mitochondria and STIM-1 could be targets for the treatment of hypertension. Project supported by the following grants to AGG: SAF 2010-21795, MINECO, Spain; Fundación Teófilo Hernando, Madrid.