Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis

Autor: Ping Li, Baolin Liu, Meng-Ru Sun, Yi Li, Hua Yang, Hui-Min Zhu, Yu-Fan Feng, Yu-Chen Li, Xiao-Tian Liu
Rok vydání: 2021
Předmět:
0301 basic medicine
Sod2
superoxide dismutase 2
OXPHOS
oxidative phosphorylation
Clinical Biochemistry
PGC-1α
Biochemistry
CPT-1
carnitine palmitoyltransferase-1
NAO
nonyl acridine orange
Mice
0302 clinical medicine
MCU
mitochondrial calcium uniporter
Songorine
OCR
oxygen consumption rate
NRF1
lcsh:QH301-705.5
HO-1
heme oxygenase-1
chemistry.chemical_classification
Cardioprotection
lcsh:R5-920
Kelch-Like ECH-Associated Protein 1
Organelle Biogenesis
NAC
n-acetylcysteine
Chemistry
ORAI1
TFAM
mitochondrial transcription factor A
respiratory system
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Cell biology
Septic cardiomyopathy
NRVMs
neonatal rat ventricular myocytes
LPS
lipopolysaccharide
NRF1
nuclear respiratory factor-1
lcsh:Medicine (General)
Research Paper
NF-E2-Related Factor 2
ETC
electron transport chain
TCA
tricarboxylic acid
ARE
antioxidant response element
Oxidative phosphorylation
Nrf2
03 medical and health sciences
ROS
reactive oxygen species
Alkaloids
Mitochondrial biogenesis
GSK3β
glycogen synthase kinase 3β
Sepsis
Animals
Reactive oxygen species
CRAC
calcium release-activated calcium
ECAR
extracellular acidification rate
Nrf2
NF-E2-p45-related factor 2
Organic Chemistry
TFAM
KEAP1
mtDNA
mitochondrial DNA
030104 developmental biology
lcsh:Biology (General)
3-MA
3-methyladenine
030217 neurology & neurosurgery
Zdroj: Redox Biology
Redox Biology, Vol 38, Iss, Pp 101771-(2021)
ISSN: 2213-2317
DOI: 10.1016/j.redox.2020.101771
Popis: Septic cardiomyopathy is characterized by impaired contractive function with mitochondrial dysregulation. Songorine is a typical active C20-diterpene alkaloid from the lateral root of Aconitum carmichaelii, which has been used for the treatment of heart failure. This study investigated the protective role of songorine in septic heart injury from the aspect of mitochondrial biogenesis. Songorine (10, 50 mg/kg) protected cardiac contractive function against endotoxin insult in mice with Nrf2 induction. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial reactive oxygen species (ROS) production and redistributed STIM1 to interact with Orai1 for the formation of calcium release-activated calcium (CRAC) channels, mediating calcium influx, which were prevented by songorine, likely due to ROS suppression. Songorine activated Nrf2 by promoting Keap1 degradation, having a contribution to enhancing antioxidant defenses. When LPS shifted metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) in cardiomyocytes, songorine upregulated mitochondrial genes involved in fatty acid β-oxidation, tricarboxylic acid (TCA) cycle and electron transport chain in a manner dependent on Nrf2, resultantly protecting the capability of OXPHOS. Songorine increased luciferase report gene activities of nuclear respiratory factor-1 (Nrf1) and mitochondrial transcription factor A (Tfam) dependently on Nrf2, indicative of the regulation of Nrf2/ARE and NRF1 signaling cascades. Songorine promoted PGC-1α binding to Nrf2, and the cooperation was required for songorine to activate Nrf2/ARE and NRF1 for the control of mitochondrial quality and quantity. In support, the beneficial effects of songorine on cardioprotection and mitochondrial biogenesis were diminished by cardiac Nrf2 deficiency in mice subjected to LPS challenge. Taken together, these results showed that Nrf2 transcriptionally promoted mitochondrial biogenesis in cooperation with PGC-1α. Songorine activated Nrf2/ARE and NRF1 signaling cascades to rescue cardiomyocytes from endotoxin insult, suggesting that protection of mitochondrial biogenesis was a way for pharmacological intervention to prevent septic heart injury.
Graphical abstract Image 1
Highlights • Mitochondrial ROS increased calcium influx through CRAC channels. • Nrf2 interacted with PGC-1α to regulate mitochondrial biogenesis. • Songorine activated Nrf2 by promoting Keap1 degradation. • Songorine regulated Nrf2/ARE and PGC-1α cascades to protect cardiac function.
Databáze: OpenAIRE
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