Hydrogen peroxide depolarizes mitochondria and inhibits IP3-evoked Ca2+ release in the endothelium of intact arteries

Xun Zhang,Matthew D Lee,Calum Wilson,John G Mccarron

doi:10.1016/j.ceca.2019.102108

Xun Zhang, Matthew D Lee + Show 2 more

Open Access

https://doi.org/10.1016/j.ceca.2019.102108

Copy DOI

Journal: Cell calcium	Publication Date: Nov 1, 2019
Citations: 21	License type: cc-by

Affiliation: University of Strathclyde

Abstract

Hydrogen peroxide (H2O2) is a mitochondrial-derived reactive oxygen species (ROS) that regulates vascular signalling transduction, vasocontraction and vasodilation. Although the physiological role of ROS in endothelial cells is acknowledged, the mechanisms underlying H2O2 regulation of signalling in native, fully-differentiated endothelial cells is unresolved. In the present study, the effects of H2O2 on Ca2+ signalling were investigated in the endothelium of intact rat mesenteric arteries. Spontaneous local Ca2+ signals and acetylcholine evoked Ca2+ increases were inhibited by H2O2. H2O2 inhibition of acetylcholine-evoked Ca2+ signals was reversed by catalase. H2O2 exerts its inhibition on the IP3 receptor as Ca2+ release evoked by photolysis of caged IP3 was supressed by H2O2. H2O2 suppression of IP3-evoked Ca2+ signalling may be mediated by mitochondria. H2O2 depolarized mitochondria membrane potential. Acetylcholine-evoked Ca2+ release was inhibited by depolarisation of the mitochondrial membrane potential by the uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) or complex 1 inhibitor, rotenone. We propose that the suppression of IP3-evoked Ca2+ release by H2O2 arises from the decrease in mitochondrial membrane potential. These results suggest that mitochondria may protect themselves against Ca2+ overload during IP3-linked Ca2+ signals by a H2O2 mediated negative feedback depolarization of the organelle and inhibition of IP3-evoked Ca2+ release.

Highlights

The endothelium is the single layer of cells that lines the entire cardiovascular system and it is exposed constantly to a wide range of mechanical and chemical stimuli
As spontaneous Ca2+ release arises from IP3-receptor activity [44,80,81], these results suggest that H2O2 may suppress Ca2+ release from the internal Ca2+ store
ACh (100 nM) evoked substantial Ca2+ signals that were heterogeneous across the endothelium and the amplitude and frequency of Ca2+ oscillations varied across cells. (Fig. 2A)

Summary

Introduction

The endothelium is the single layer of cells that lines the entire cardiovascular system and it is exposed constantly to a wide range of mechanical and chemical stimuli. The endothelium responds to these stimuli by releasing Ca2+-dependent vasoactive factors that include nitric oxide, prostacyclin, endothelium-derived contracting factors, von Willebrand factor, tissue plasminogen activator and endothelial derived hyperpolarising factor (1, 2). These vasoactive factors allow the endothelium to regulate almost all cardiovascular activities including vascular tone, immune responses, angiogenesis and vascular remodelling [1]. ROS modulates endothelial cell growth, proliferation, endothelium-dependent relaxation, cytoskeletal reorganization, inflammatory responses and endothelium-regulated vascular remodelling. H2O2 is a small and non-polar molecule produced by several cell processes that include mitochondria and NADPH oxidase [17,29,76]. O2 is not membrane permeable, H2O2 can diffuse across biological membranes or may cross membrane boundaries via channels like aquaporins [8] to regulate physiological and pathological cellular processes [3,62,75,85]

Methods

Results

Conclusion