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NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model
Beibei Luo1, Bo Li1, Wenke Wang1
1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, China.
Background:
Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is associated with metabolic disorder and cell death, which are important triggers in diabetic cardiomyopathy (DCM). We aimed to explore whether NLRP3 inflammasome activation contributes to DCM and the mechanism involved.
Methods:
Type 2 diabetic rat model was induced by high fat diet and low dose streptozotocin. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Gene silencing therapy was used to investigate the role of NLRP3 in the pathogenesis of DCM. High glucose treated H9c2 cardiomyocytes were used to determine the mechanism by which NLRP3 modulated the DCM. The cell death in vitro was detected by TUNEL and EthD-III staining. TXNIP-siRNA and pharmacological inhibitors of ROS and NF-kB were used to explore the mechanism of NLRP3 inflammasome activation.
Results:
Diabetic rats showed severe metabolic disorder, cardiac inflammation, cell death, disorganized ultrastructure, fibrosis and excessive activation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase-1, activated caspase-1 and mature interleukin-1β (IL-1β). Evidence for pyroptosis was found in vivo, and the caspase-1 dependent pyroptosis was found in vitro. Silencing of NLRP3 in vivo did not attenuate systemic metabolic disturbances. However, NLRP3 gene silencing therapy ameliorated cardiac inflammation, pyroptosis, fibrosis and cardiac function. Silencing of NLRP3 in H9c2 cardiomyocytes suppressed pyroptosis under high glucose. ROS inhibition markedly decreased nuclear factor-kB (NF-kB) phosphorylation, thioredoxin interacting/inhibiting protein (TXNIP), NLRP3 inflammasome, and mature IL-1β in high glucose treated H9c2 cells. Inhibition of NF-kB reduced the activation of NLRP3 inflammasome. TXNIP-siRNA decreased the activation of caspase-1 and IL-1β.
Conclusion:
NLRP3 inflammasome contributed to the development of DCM. NF-κB and TXNIP mediated the ROS-induced caspase-1 and IL-1β activation, which are the effectors of NLRP3 inflammasome. NLRP3 gene silencing may exert a protective effect on DCM.
Insights
NLRP3 inflammasome activation contributes to diabetic cardiomyopathy (DCM) by promoting cardiac inflammation and pyroptosis. Targeting NLRP3 offers a potential therapeutic strategy for DCM.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Metabolic Disease Mechanisms
Background:
- Diabetic cardiomyopathy (DCM) is linked to metabolic disorder and cell death.
- Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is implicated in these processes.
Purpose of the Study:
- To investigate the role of NLRP3 inflammasome activation in DCM pathogenesis.
- To elucidate the underlying mechanisms involving reactive oxygen species (ROS), NF-κB, and TXNIP.
Main Methods:
- A type 2 diabetic rat model was established using high-fat diet and streptozotocin.
- Cardiac function, inflammation, and cell death were assessed.
- NLRP3 gene silencing and pharmacological inhibitors were employed in vivo and in vitro (H9c2 cardiomyocytes).
Main Results:
- NLRP3 inflammasome, ASC, caspase-1, and IL-1β were activated in diabetic rats.
- NLRP3 silencing ameliorated cardiac inflammation, pyroptosis, and fibrosis, improving cardiac function.
- ROS inhibition reduced NF-κB phosphorylation, TXNIP, NLRP3 inflammasome, and IL-1β activation.
Conclusions:
- NLRP3 inflammasome activation is a key contributor to DCM development.
- NF-κB and TXNIP mediate ROS-induced NLRP3 inflammasome activation.
- NLRP3 gene silencing demonstrates potential therapeutic benefits for DCM.
