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Zinc Up‐regulates Nox1 Function by Increasing Mitochondrial ROS to Induce Senescence of Vascular Smooth Muscle Cells
Author(s) -
Huang Jingwen,
Feresin Rafaela G.,
Salazar Gloria
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.802.3
Subject(s) - nox4 , mitochondrial ros , reactive oxygen species , senescence , nox1 , mitochondrion , microbiology and biotechnology , oxidative stress , chemistry , vascular smooth muscle , nadph oxidase , biology , biochemistry , endocrinology , smooth muscle
Zinc, an essential trace element, plays a significant role in the regulation of multiple cellular processes. We previously demonstrated that zinc overload up‐regulated reactive oxygen species (ROS) levels causing senescence. However, the source of ROS that mediates zinc effects was not determined. Objectives Thus, the purpose of this study was to investigate whether increased ROS levels and senescence induced by zinc is attributed to increased mitochondrial ROS (mtROS), ROS produced by NADPH oxidases (Nox) or both. Methods Vascular smooth muscle cells (VSMCs) treated with 50 μM zinc were incubated with 2′,7′‐dichlorodihydrofluorescein diacetate (H 2 DCFDA) and MitoSox to measure hydrogen peroxide and mtROS, respectively. Western blots were used to determine the expression of Nox1, Nox4, antioxidant enzymes and the senescence markers, p21 and p53. After three days of the treatment, senescence was determined by measuring senescence associated β‐galactosidase (SA‐β‐gal) activity. Results We found that zinc overload increased the expression of Nox1, but not Nox4, and promoted the accumulation of zinc in the mitochondria causing increased mtROS generation. Blocking mtROS with MitoTEMPO reduced Nox1 expression and senescence induced by zinc. Conclusions Increased zinc levels promote mtROS generation, which up‐regulates Nox1 expression increasing cytosolic ROS levels and inducing senescence of VSMCs. Support or Funding Information This study was supported in part by the American Heart Association (14GRNT20180028), the American Federation for Aging Research (AFAR) and the Florida State University Council on Research and Creativity (COFRS).