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Vascular Protection by Exercise in Obesity: Inflammasome-associated Mechanisms
Jonghae Lee1, Junyoung Hong1, Michihisa Umetani2
1Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX.
Purpose:
The nodlike receptor family pyrin domain containing 3 (NLRP3) inflammasome is a critical player in vascular pathology as it regulates caspase-1-mediated interleukin (IL)-1β processing. Physical activity ameliorates obesity-induced inflammation and vascular dysfunction, but the mechanisms responsible for these positive changes are incompletely understood. Here, the protective effect of physical activity on the inflammasome-associated vascular dysfunction in obesity and its putative mechanisms were investigated.
Methods:
Mice were fed a control low-fat diet (LFD) or a high-fat diet (HFD; 45% of calories from fat) and provided with running wheel access (LF-RUN or HF-RUN) or denied wheel access for our sedentary condition (LF-SED or HF-SED). The NLRP3 inflammasome-associated pathway, including NLRP3, caspase-1, and IL-1β, in mice aorta was examined by RT-qPCR and FLICA and DAB staining. The protein expression of zonula occluden-1 (ZO-1), ZO-2, adiponectin (APN), and adiponectin receptor 1 (AdipoR1) in aortic endothelial cells was determined by immunofluorescence double staining. Intracellular reactive oxidative stress and nitric oxide (NO) production were monitored with fluorescence probes, dihydroethidium, and diaminofluorecein.
Results:
HFD increased caspase-1 and IL-1β at mRNA and protein levels in endothelial cells of the aorta, and this was attenuated by voluntary running. HFD decreased ZO-1 and ZO-2 expression and reduced APN and AdipoR1 signaling; these were restored by running. The elevated intracellular superoxide (O2) production observed in HF-SED was ameliorated in HF-RUN. Finally, HF-RUN improved NO production in the aorta compared with HF-SED.
Conclusions:
Our findings suggest that voluntary running ameliorates mechanisms associated with vascular dysfunction by suppressing NLRP3 inflammasome, improving NO production, and reducing oxidative stress. Such benefits of physical activity may be, at least in part, associated with APN-AdipoR1 signaling and tight junction protein expression.
Insights
Physical activity, such as voluntary running, mitigates vascular dysfunction in obesity by reducing NLRP3 inflammasome activation and oxidative stress. These benefits are linked to improved nitric oxide production and adiponectin signaling.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Metabolic Disease
Background:
- The NLRP3 inflammasome plays a key role in obesity-induced vascular pathology.
- Physical activity is known to reduce inflammation and improve vascular function, but underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the protective effects of physical activity on inflammasome-associated vascular dysfunction in obesity.
- To elucidate the mechanisms by which physical activity ameliorates obesity-induced vascular issues.
Main Methods:
- Mice were fed high-fat or control diets and given access to running wheels or kept sedentary.
- NLRP3 inflammasome components (NLRP3, caspase-1, IL-1β) and tight junction proteins were analyzed in mouse aortas.
- Oxidative stress and nitric oxide production were measured using fluorescence probes.
Main Results:
- High-fat diet increased NLRP3 inflammasome activation and oxidative stress, while reducing tight junction proteins and nitric oxide production.
- Voluntary running attenuated inflammasome activation, decreased oxidative stress, and restored tight junction protein expression and nitric oxide levels.
- Running also improved adiponectin-adiponectin receptor 1 signaling in aortic endothelial cells.
Conclusions:
- Voluntary running ameliorates obesity-associated vascular dysfunction by suppressing the NLRP3 inflammasome and oxidative stress.
- Physical activity's benefits may involve enhanced nitric oxide production and restored adiponectin-adiponectin receptor 1 signaling.
- Improved tight junction protein expression is another potential mechanism contributing to vascular protection from exercise.
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