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NLRC5 deficiency promotes myocardial damage induced by high fat diet in mice through activating TLR4/NF-κB
1Department of Cardiology, Huai'an First Affiliated Hospital, Nanjing Medical University, Huai'an 223300, China.
Abstract:
The metabolic syndrome could be induced by high fat diet, leading to cardiovascular diseases, such as myocardial damage. Inflammation response and oxidative stress have been reported to be involved in high fat-induced heart injury, and the molecular mechanism is not fully understood. The NOD-like protein family member, NLRC5, could interact with IKKα to inhibit IKK complex activation. In our study, high fat diet-feeding mice showed cardiac fibrosis, inflammation and oxidative stress through collagen accumulation, TLR4/NF-κB and MAPKs signaling pathways activation. NLRC5 knockout mice fed with high fat showed accelerated fibrosis and inflammation response by promoting α-SMA, Collagen I, Collagen III, TLR4/MyD88, phosphorylated IKKα, IκBα and NF-κB expression. And no effect on oxidative stress was observed in wild type and NLRC5-deficiency samples in in vivo studies. Moreover, NLRC5-knockout and -knockdown cardiac muscle cells challenged with LPS also exhibited aggravated fibrosis levels and inflammatory response without any influences on ROS production in in vitro studies. In conclusion, the findings indicated that NLRC5 showed important effects on high fat-induced heart injury via fibrosis and inflammation modulation, providing an essential target for improving myocardial damage induced by high fat diet.
Insights
NLRC5 deficiency exacerbates high fat diet-induced heart injury, accelerating cardiac fibrosis and inflammation. This highlights NLRC5
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Metabolic Syndrome Research
Background:
- High-fat diets induce metabolic syndrome and cardiovascular diseases, including myocardial damage.
- Inflammation and oxidative stress are implicated in high-fat diet-induced heart injury, but mechanisms remain unclear.
- NLRC5 (NOD-like protein family member 5) can inhibit IKK complex activation by interacting with IKKα.
Purpose of the Study:
- To investigate the role of NLRC5 in high-fat diet-induced cardiac injury.
- To elucidate the molecular mechanisms underlying NLRC5's effect on cardiac fibrosis, inflammation, and oxidative stress.
Main Methods:
- Utilized high-fat diet-fed mice models, including NLRC5 knockout mice.
- Assessed cardiac fibrosis, inflammation, and oxidative stress markers (e.g., collagen, α-SMA, TLR4/NF-κB, MAPKs, ROS).
- Employed in vitro studies using NLRC5-knockout/knockdown cardiac muscle cells stimulated with LPS.
Main Results:
- High-fat diet induced cardiac fibrosis, inflammation, and oxidative stress in wild-type mice.
- NLRC5 knockout mice exhibited exacerbated cardiac fibrosis and inflammation, with increased expression of fibrosis and inflammatory markers.
- No significant effect on oxidative stress was observed in either in vivo or in vitro studies related to NLRC5 deficiency.
- In vitro studies confirmed aggravated fibrosis and inflammation in NLRC5-deficient cardiac cells without affecting ROS production.
Conclusions:
- NLRC5 plays a protective role against high-fat diet-induced heart injury.
- NLRC5 modulates cardiac fibrosis and inflammation, but not oxidative stress, in the context of high-fat diet.
- Targeting NLRC5 may offer a therapeutic strategy for mitigating myocardial damage caused by high-fat diets.
