ALDH2 mitigates LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING pathway.
ALDH2
Apoptosis
Cardiac dysfunction
Inflammation
Lipopolysaccharide
cGAS/STING
Journal
Molecular medicine (Cambridge, Mass.)
ISSN: 1528-3658
Titre abrégé: Mol Med
Pays: England
ID NLM: 9501023
Informations de publication
Date de publication:
20 Dec 2023
20 Dec 2023
Historique:
received:
19
09
2023
accepted:
10
12
2023
medline:
21
12
2023
pubmed:
21
12
2023
entrez:
21
12
2023
Statut:
epublish
Résumé
Sepsis is a severe syndrome of organ dysfunction that often leads to cardiac dysfunction and endangers life. The role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in LPS-induced myocardial injury is unclear. The purpose of this study was to assess the role of ALDH2 in lipopolysaccharide (LPS)-induced myocardial injury and the regulatory mechanism and to identify potential therapeutic strategies for treating this condition. An in vivo model was established by 12 h of LPS (10 mg/kg, intraperitoneal injection) stimulation, and an in vitro model was generated by stimulating H9C2 cells with LPS (10 μg/ml) for 12 h. We then used the ALDH2 activator Alda-1 and the ALDH2 inhibitor daidzin to assess their effects on LPS-induced cardiac injury. Cardiac function in mice was evaluated by using cardiac ultrasound. We used various methods to evaluate inflammation, apoptosis, and oxidative stress, including ELISA, flow cytometry, JC-1 staining, Western blotting, and DCFH-DA staining. Additionally, we used a small interfering RNA (siRNA) to knock down cyclic GMP-AMP synthase (cGAS) to further investigate the relationship between ALDH2 and cGAS in LPS-induced cardiac injury. LPS-induced cardiac dysfunction and increased the levels of the cardiac injury markers creatine kinase-MB (CKMB) and lactate dehydrogenase (LDH) in vivo. This change was accompanied by an increase in reactive oxygen species (ROS) levels, which exacerbated the oxidative stress response and regulated apoptosis through cleaved caspase-3, BAX, BCL-2. The expression of inflammatory cytokines such as IL-6/IL-1β/TNF-α was also upregulated. However, these effects were reversed by pretreatment with Alda-1 via the inhibition of cGAS/stimulator of interferon genes (STING) signaling pathway. Interestingly, LPS, Alda-1 and daidzin altered the activity of ALDH2 but did not regulate its protein expression. Knocking down cGAS in H9C2 cardiomyocytes alleviated LPS-induced cardiac inflammation, apoptosis, and ROS production and weakened the synergistic effect of daidzin. We demonstrated that ALDH2 alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING signaling pathway, thereby protecting against LPS-induced cardiac injury. This study identifies a novel therapeutic approach for treating sepsis-induced cardiomyopathy (SIC).
Sections du résumé
BACKGROUND
BACKGROUND
Sepsis is a severe syndrome of organ dysfunction that often leads to cardiac dysfunction and endangers life. The role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in LPS-induced myocardial injury is unclear. The purpose of this study was to assess the role of ALDH2 in lipopolysaccharide (LPS)-induced myocardial injury and the regulatory mechanism and to identify potential therapeutic strategies for treating this condition.
METHODS
METHODS
An in vivo model was established by 12 h of LPS (10 mg/kg, intraperitoneal injection) stimulation, and an in vitro model was generated by stimulating H9C2 cells with LPS (10 μg/ml) for 12 h. We then used the ALDH2 activator Alda-1 and the ALDH2 inhibitor daidzin to assess their effects on LPS-induced cardiac injury. Cardiac function in mice was evaluated by using cardiac ultrasound. We used various methods to evaluate inflammation, apoptosis, and oxidative stress, including ELISA, flow cytometry, JC-1 staining, Western blotting, and DCFH-DA staining. Additionally, we used a small interfering RNA (siRNA) to knock down cyclic GMP-AMP synthase (cGAS) to further investigate the relationship between ALDH2 and cGAS in LPS-induced cardiac injury.
RESULTS
RESULTS
LPS-induced cardiac dysfunction and increased the levels of the cardiac injury markers creatine kinase-MB (CKMB) and lactate dehydrogenase (LDH) in vivo. This change was accompanied by an increase in reactive oxygen species (ROS) levels, which exacerbated the oxidative stress response and regulated apoptosis through cleaved caspase-3, BAX, BCL-2. The expression of inflammatory cytokines such as IL-6/IL-1β/TNF-α was also upregulated. However, these effects were reversed by pretreatment with Alda-1 via the inhibition of cGAS/stimulator of interferon genes (STING) signaling pathway. Interestingly, LPS, Alda-1 and daidzin altered the activity of ALDH2 but did not regulate its protein expression. Knocking down cGAS in H9C2 cardiomyocytes alleviated LPS-induced cardiac inflammation, apoptosis, and ROS production and weakened the synergistic effect of daidzin.
CONCLUSION
CONCLUSIONS
We demonstrated that ALDH2 alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING signaling pathway, thereby protecting against LPS-induced cardiac injury. This study identifies a novel therapeutic approach for treating sepsis-induced cardiomyopathy (SIC).
Identifiants
pubmed: 38124089
doi: 10.1186/s10020-023-00769-5
pii: 10.1186/s10020-023-00769-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
171Subventions
Organisme : National Natural Science Foundation of China
ID : 82303712
Organisme : National Natural Science Foundation of China
ID : 81871611
Organisme : the Foundation of Sichuan Provincial Science and Technology
ID : 2022YFS0602
Organisme : Hainan Province Science and Technology Special Fund
ID : ZDKJ202004
Organisme : Hainan Province Science and Technology Special Fund
ID : ZDKJ2021038
Organisme : the Foundation of Sichuan Provincial People's Hospital
ID : 2022QN43
Informations de copyright
© 2023. The Author(s).
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