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Effect of Bosentan on Reductive Stress Induced Endothelin‐1/eNOS Dysfunction in Cardiomyocytes
Author(s) -
Khanderao Gaytri Deepti,
Davidson Christopher J,
Varadharaj Saradhadevi,
Benjamin Ivor J,
Soorappan Rajasekaran Namakkal
Publication year - 2010
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.24.1_supplement.1001.14
Subject(s) - oxidative stress , enos , glutathione , chemistry , nitric oxide , reactive oxygen species , thioredoxin , endothelin 1 , intracellular , nad+ kinase , bosentan , medicine , receptor , endocrinology , biochemistry , microbiology and biotechnology , endothelin receptor , biology , nitric oxide synthase , organic chemistry , enzyme
Impairments of redox balance in cells and sub‐cellular structures can lead to either oxidative or reductive stress. While oxidative stress has many known, damaging effects, specific cellular and molecular responses to a reducing environment remain elusive. Reductive stress (RS) is defined as the supra‐physiological levels of intracellular reducing power (GSH/GSSG, NAD(P)H/NAD(P), Cysteine/Cystine). In mouse hearts exhibiting protein aggregation and RS (Rajasekaran et.al, Cell, 2007), transcriptional products for endothelin (ET) and its receptors (ET‐A/ET‐B) were significantly upregulated along with a profound decrease in the endothelial nitric oxide synthetase (eNOS). Using potential oxidizing/reducing agents, we have established oxidative/reductive stress models in HL‐1 cardiomyocytes in vitro. The redox state was determined by measuring the reduced/oxidized levels of glutathione (GSH/GSSG) and reactive oxygen species (ROS) using fluorescent probes. Effects of RS on cardiomyocytes hypertrophy (ANF/BNF), contractility and cell survival/death pathways were investigated. Results indicated significant impairment of Et‐1/eNOS system under RS condition, suggesting a direct role for RS on the regulation of Et‐1/eNOS function. Further, we have used bosentan, a specific antagonist/inhibitor of ET receptors, to rescue the changes associated with RS in HL‐1 cardiomyocytes.