Zinc-dependent changes in oxidative and endoplasmic reticulum stress during cardiomyocyte hypoxia/reoxygenation.

Abstract:

:Myocardial zinc dyshomeostasis is associated with caspase-3 activation, ErbB2 degradation and apoptosis during hypoxia/reoxygenation. Zinc pyrithione replenishes intracellular zinc, suppresses caspase-3, augments ErbB2 levels and improves cell survival. We hypothesize that zinc is capable of modulating redox and endoplasmic reticulum (ER) stress in the setting of cardiomyocyte hypoxia-reoxygenation. Hypoxia/reoxygenation lowered intracellular zinc, increased ER as well as oxidative stress in H9c2 cells, both of which were effectively attenuated by zinc supplementation. Silencing of gp91phox attenuated oxidative and ER stress, decreased caspase-3 activation and improved cell survival. Mimicking the oxidative insult using 50 μM H2O2 increased the caspase-3 activity that correlated with decreased ErbB2 levels, concomitant with augmented ER stress. N-acetyl cysteine (NAC) administration completely suppressed ER stress as well as caspase-3 activity. Zinc depletion using TPEN also resulted in lowered ErbB2 and increased apoptosis, along with NOX2 mRNA upregulation, increased oxidative and ER stress. Repletion with zinc suppressed NOX2 mRNA, lowered oxidative as well as ER stress and decreased cell death. These results suggest that zinc dyshomeostasis, along with oxidative stress contribute to the unfolded protein response during myocardial H/R and that zinc replenishment corrects zinc homeostasis, alleviates associated stress and improves cardiomyocyte survival.

journal_name

Biol Chem

journal_title

Biological chemistry

authors

Bodiga VL,Vemuri PK,Nimmagadda G,Bodiga S

doi

10.1515/hsz-2020-0167

subject

Has Abstract

pub_date

2020-10-25 00:00:00

pages

1257-1271

issue

11

eissn

1431-6730

issn

1437-4315

pii

/j/bchm.just-accepted/hsz-2020-0167/hsz-2020-0167.

journal_volume

401

pub_type

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