Tyrosine kinase Fyn promotes apoptosis after intracerebral hemorrhage in rats by activating Drp1 signaling.
Animals
Apoptosis
/ physiology
Apoptosis Regulatory Proteins
/ genetics
Blood-Brain Barrier
Brain
/ metabolism
Brain Edema
/ etiology
Cerebral Hemorrhage
/ enzymology
Disease Models, Animal
Down-Regulation
Dynamins
/ antagonists & inhibitors
Gene Knockdown Techniques
Humans
Male
Nerve Tissue Proteins
/ biosynthesis
Phosphorylation
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-fyn
/ biosynthesis
Quinazolinones
/ pharmacology
RNA Interference
RNA, Small Interfering
/ genetics
Rats
Rats, Sprague-Dawley
Signal Transduction
/ physiology
Specific Pathogen-Free Organisms
Apoptosis
Drp1
Inflammatory
Intracerebral hemorrhage
Tyrosine kinase Fyn
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
08
03
2020
accepted:
08
12
2020
revised:
30
11
2020
pubmed:
8
1
2021
medline:
15
12
2021
entrez:
7
1
2021
Statut:
ppublish
Résumé
Tyrosine kinase Fyn is a member of the Src kinase family, which is involved in neuroinflammation, apoptosis, and oxidative stress. Its role in intracerebral hemorrhage (ICH) is not fully understood. In this study, we found that Fyn was significantly elevated in human brain tissue after ICH. Accordingly, we investigated the role of Fyn in a rat ICH model, which was constructed by injecting blood into the right basal ganglia. In this model, Fyn expression was significantly upregulated in brain tissue adjacent to the hematoma. SiRNA-induced Fyn knockdown was neuroprotective for secondary cerebral damage, as demonstrated by reduced brain edema, suppression of the modified neurological severity score, and mitigation of blood-brain barrier permeability and neuronal damage. Fyn downregulation reduced apoptosis following ICH, as indicated by downregulation of apoptosis-related proteins AIF, Cyt.c, caspase 3, and Bax; upregulation of anti-apoptosis-related protein Bcl-2; and decreased tunnel staining. Mdivi-1, a Drp1 inhibitor, reversed Fyn overexpression induced pro-apoptosis. However, Fyn did not significantly affect inflammation-related proteins NF-κB, TNF-α, caspase 1, MPO, IL-1β, or IL-18 after ICH. Fyn activated Drp1 signaling by phosphorylating Drp1 at serine 616, which increased apoptosis after ICH in rats. This study clarifies the relationship between Fyn, apoptosis, and inflammation following ICH and provides a new strategy for exploring the prevention and treatment of ICH. KEY MESSAGES: ICH induced an increase in Fyn expression in human and rat cerebral tissues. Knockdown of Fyn prevented cerebral damage following ICH. Inhibition of Fyn had no significant effects on inflammatory responses. However, the downregulation of Fyn exerted neuroprotective effects on apoptosis. Fyn perturbed ICH-induced cell apoptosis by interacting with and phosphorylating (Ser616) Drp1 in a rat ICH model.
Identifiants
pubmed: 33409551
doi: 10.1007/s00109-020-02022-6
pii: 10.1007/s00109-020-02022-6
doi:
Substances chimiques
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
0
Apoptosis Regulatory Proteins
0
Nerve Tissue Proteins
0
Quinazolinones
0
RNA, Small Interfering
0
FYN protein, human
EC 2.7.10.2
Fyn protein, rat
EC 2.7.10.2
Proto-Oncogene Proteins c-fyn
EC 2.7.10.2
Dnm1l protein, rat
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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