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Up‐regulation of Nox4 expression in DUSP4−/− hearts is a critical factor in modulating cardiovascular function under oxidative stress
Author(s) -
Lamb Joseph P,
BarajasEspinoza Alma,
Basye Ariel,
Angelos Mark,
Chen ChunAn
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.696.12
Subject(s) - nox4 , oxidative stress , reactive oxygen species , endothelial dysfunction , microbiology and biotechnology , p38 mitogen activated protein kinases , nadph oxidase , gene silencing , chemistry , biology , protein kinase a , medicine , biochemistry , kinase , gene
Increased production of reactive oxygen species (ROS) and decreased antioxidant activity contributing to the cellular redox imbalance is the primary pathogenic factor of ischemia/reperfusion (I/R) injury and endothelial dysfunction. Redox imbalance leads to cellular dysfunction through protein oxidation, DNA damage, and lipid peroxidation. During I/R in hearts, NADPH oxidases (Noxs) are one of the major sources of ROS generation. The burst of ROS production during reperfusion activates stress‐response elements, including the p38 kinase whose over‐activation is one negative contributor to cardiovascular dysfunction, especially I/R injury. Previously we demonstrated that N‐acetyl cysteine (NAC) pre‐treatment up‐regulates dual specificity phosphatase 4 (DUSP4) expression in endothelial cells, regulating p38 and ERK1/2 activities, thus providing a protective effect against oxidative stress. Here, endothelial cells under hypoxia/reoxygenation (H/R) insult and isolated heart I/R injury were used to investigate the role of DUSP4 on the modulation of ROS generation. DUSP4 gene silencing in endothelial cells augments their sensitivity to H/R‐induced apoptosis (45.81% ± 5.23%). This sensitivity is diminished via the inhibition of p38 activity (total apoptotic cells drop to 17.47% ± 1.45%). DUSP4 gene silencing contributes to the increase in superoxide generation from cells. Isolated Langendorff‐perfused mouse hearts were subjected to global I/R injury. DUSP4−/− hearts had larger infarct size than WT. This increase significantly correlates with reduced functional recovery (assessed by: RPP%, LVDP%, HR%, dP/dtmax, low CF%, and a higher initial LVEDP). The level of Nox4 protein and mRNA expression is up‐regulated in DUSP4−/− hearts. This data strongly suggests that DUSP4 is of critical importance in modulating myocardial function after I/R injury and the reason why DUSP4−/− hearts are more susceptible to I/R injury. Thus, Nox4 modulation by DUSP4 provides a therapeutic target.