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Circadian rhythm disruption induces cardiac hypertrophy via promoting the mtDNA release-activated cGAS-STING pathway
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DOI：10.1016/j.bcp.2026.118309.png)
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Abstract
En 中文
Circadian rhythm disruption (CRD) is highly prevalent and has been associated with an increased risk of cardiovascular disease. However, the molecular mechanisms linking CRD to cardiac injury remain incompletely understood. In this study, a chronic light-induced CRD mouse model and an in vitro model were established using norepinephrine (NE)-treated neonatal rat cardiomyocytes (NRCMs) to investigate the progression of CRD-induced cardiac remodeling and the underlying mechanisms. CRD disrupted feeding rhythms, reduced cardiac Bmal1 and Clock mRNA expression, and altered body weight gain. Echocardiographic analysis revealed a progressive pattern of cardiac dysfunction characterized by early diastolic impairment, transient compensation, and subsequent pathological remodeling with systolic dysfunction. CRD was associated with sustained myocardial NE elevation, mitochondrial oxidative stress, cytosolic mitochondrial DNA (mtDNA) accumulation, and activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. Cardiac-specific STING knockdown significantly improved cardiac function and attenuated inflammation and hypertrophic remodeling in CRD mice. Consistently, NE-treated NRCMs exhibited mitochondrial dysfunction, cytosolic mtDNA accumulation, and activation of cGAS-STING signaling. Reducing mtDNA availability or pharmacologically inhibiting cGAS-STING signaling significantly attenuated NE-induced inflammatory and hypertrophic responses in vitro. These results indicate that chronic light-induced CRD promotes cardiac remodeling and dysfunction by inducing mitochondrial injury, activating mtDNA-dependent cGAS-STING signaling, and eliciting subsequent inflammatory responses. Targeting the mtDNA-cGAS-STING pathway may therefore represent a promising therapeutic strategy for CRD-associated cardiac injury.
Keywords:
Circadian rhythm disruption
Cardiac hypertrophy
Norepinephrine
cGAS-STING
cGAS
cyclic GMP-AMP synthase
CON
control
CRD
circadian rhythm disruption
CytB
cytochrome b
E/A
Early transmitral velocity/Atrial contraction velocity
EtBr
Ethidium Bromide
Gpx-1
glutathione peroxidase 1
HE
hematoxylin-eosin
Hmox1
heme oxygenase 1
HW/TL
heart weight to tibia length
IVCT
isovolumic contraction time
IVRT
isovolumic relaxation time
LDH
lactate dehydrogenase
LVAW
left ventricular anterior wall thickness
LVPW
left ventricular posterior wall thickness
MDA
malondialdehyde
mtDNA
mitochondrial DNA
ND1
NADH dehydrogenase subunit 1
NE
norepinephrine
NRCMs
neonatal rat cardiomyocytes
Sod-1
superoxide dismutase 1
STING
stimulator of interferon genes
TH
tyrosine hydroxylase
WGA
wheat germ agglutinin
Journal
IF:
5.6
Papers:
1.3W
Citations:
3.3W
Organization
Cited Papers