Abstract
Cardiac dysfunction has been recognized as a major contributor to mortality in sepsis,
which is closely associated with inflammatory reactions. The carboxy terminus of Hsc70-interacting
protein (CHIP), a U-box E3 ubiquitin ligase, defends against cardiac injury caused
by other factors, but its role in sepsis-induced cardiac dysfunction has yet to be
determined. The present study was designed to investigate the effects of CHIP on cardiac
dysfunction caused by sepsis and the molecular mechanisms underlying these processes.
We discovered that the CHIP level decreased gradually in the heart at different time
points after septic model construction. The decline in CHIP expression of lipopolysaccharide
(LPS)-stimulated cardiomyocytes was related to c-Jun activation that inhibited the
transcription of CHIP. Functional biology experiments indicated that CHIP bound directly
to karyopherin-α 2 (KPNA2) and promoted its degradation through polyubiquitination
in cardiomyocytes. CHIP overexpression in cardiomyocytes obviously inhibited LPS-initiated
release of TNF-α and IL-6 by promoting KPNA2 degradation, reducing NF-κB translocation
into the nucleus. Consistent with the in vitro results, data obtained from animal experiments indicated that septic transgenic mice
with heart-specific CHIP overexpression showed a weaker proinflammatory response and
reduced cardiac dysfunction than septic control mice. Furthermore, we found that the
therapeutic effect of compound YL-109 on cardiac dysfunction in septic mice was due
to the upregulation of myocardial CHIP expression. These findings demonstrated that
sepsis-initiated the activation of c-Jun suppressed CHIP transcription. CHIP directly
promoted ubiquitin-mediated degradation of KPNA2, which reduced the production of
proinflammatory cytokines by inhibiting the translocation of NF-κB from the cytoplasm
into the nucleus in myocardium, thereby attenuating sepsis-induced cardiac dysfunction.
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Article info
Publication history
Published online: November 14, 2022
Accepted:
November 8,
2022
Received in revised form:
November 6,
2022
Received:
September 28,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
