Endothelial dysfunction driven by mitochondrial reactive oxygen species – proof of concept studies in CypD −/− mice

Abstract

There is growing body of evidence for a crosstalk between different enzymatic sources of oxidative stress. With the present study we sought to determine the underlying mechanisms of this crosstalk.ResultsNADPH oxidase (Nox) activation and triggered oxidative burst was assessed by chemiluminescence or fluorescence based assays and translocation of cytosolic Nox subunits in response to mitochondrial reactive oxygen species (mtROS) formation in human leukocytes. mtROS induced Nox activation was prevented by inhibitors of the mitochondrial permeability transition pore (mPTP), protein kinase C or Nox activity. mtROS induced Nox‐dependent oxidative burst was absent in white blood cells with p47phox deficiency (regulatory cytosolic Nox2 subunit) or with cyclophilin D deficiency (regulatory mPTP subunit), whereas this crosstalk was amplified in white blood cells with mitochondrial manganese superoxide dismutase deficiency (MnSOD+/−).ConclusionsOur data show that mtROS trigger the activation of phagocytic and cardiovascular NADPH oxidases, which may have fundamental consequences on immune cell activation and progression of angiotensin II‐mediated hypertension.Research supportThe present work was supported by generous financial support by the Johannes Gutenberg University and Medical Center Mainz (MAIFOR and Forschungsfonds grants to A.D.), the German Research Foundation (DFG WE 4361/3–1 to P.W. and DFG KFO142 SCHA 411/15–2 to K.S.‐K.) and the Stiftung Mainzer Herz to all authors.