Abstract 14069: QSOX1 is Involved in Resolution of Cardiac ER Stress in Mouse
Introduction: QSOX1, a sulfhydryl oxidase involved in the protein folding, is upregulated in acute heart failure.
Hypothesis: We hypothesized that QSOX1 could play a role in the endoplasmic reticulum (ER) stress in the heart in pathophysiological conditions.
Methods: QSOX1 KO (C57Bl/6 J) mice were generated using a QSOX1tm1a embryonic stem cell clone (KOMP). Acute stress was provoked by Isoproterenol (ISO, 300 mg/kg) injections for 6 or 48h, after which mice were sacrificed. Cardiac function was assessed by echocardiography. The cardiac transcripts and proteins were quantified by qPCR, and western blots, respectively. The cardiac level of oxidative stress was detected by DHE and DNPH staining.
Results: At baseline QSOX1-/- adult mice exhibited a dilated cardiomyopathy with a lower factional shortening (FS) than WT group (p=0.007). The absence of QSOX1 was associated with cardiac ER stress as illustrated with increased levels of Grp94 mRNAs (p <0.05), Grp78 (p<0.05) and p62 proteins (p <0.05) . This ER stress triggered the Unfolding Protein Response (UPR) via PERK pathway activation (high GADD34 and CHOP levels, p <0.005 vs WT). After ISO stress, QSOX1-/- mice exhibited a more severe and sustained cardiac dysfunction than WT (lower FS, p <0.02). Rapidly after ISO stress (6h), both WT and QSOX1-/- hearts activated the UPR, evidenced by eIF2 phosphorylation (p <0.01). By day 3, ER stress was undetectable in WT hearts but remained activated in QSOX1-/- (GRP78) and associated to enhanced oxidative stress. In WT, QSOX1 expression was not upregulated at 6h but at day 3 (p<0.05).
Conclusions: We show that the lack of QSOX1 induced a cardioproteinopathy characterized by an ER stress /UPR leading to apoptosis activation. When combined to acute stress, the lack of QSOX1 worsened the cardiac dysfunction through activation of oxidative stress. These data strongly suggest a role of QSOX1 in resolving acute ER stress in response to cardiac acute stress.
Author Disclosures: A. Caillard: None. M. Sadoune: None. Z. Li: None. E. Polidano: None. A. Mebazaa: None. N. Vodovar: None. J. Samuel: None.
- © 2016 by American Heart Association, Inc.