Physical activity protects NLRP3 inflammasome-associated coronary vascular dysfunction in obese mice

Abstract

Activation of the nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome mediates the release of pro‐inflammatory cytokine interleukin (IL)‐1β and thereby plays a pivotal role in the inflammatory response in vascular pathology. An active lifestyle has beneficial effects on inflammation‐associated vascular dysfunction in obesity. However, it remains unclear how physical activity regulates NLRP3 inflammasome‐mediated vascular dysfunction in obesity. Therefore, we explored the protective effect of physical activity on NLRP3 inflammasome‐associated vascular dysfunction in mouse hearts, and the potential underlying mechanisms. C57BL/6J male mice were randomly divided into four groups: (1) control low‐fat diet (LF‐SED), (2) LF diet with free access to a voluntary running wheel (LF‐RUN), (3) high‐fat diet (HF‐SED; 45% of calories from fat), and (4) HF‐RUN. We examined NLRP3 inflammasome‐related signaling pathways, nitric oxide (NO) signaling, and oxidative stress in coronary arterioles to test effects of HFD and physical activity. Voluntary running reduced NLRP3 inflammasome and its downstream effects, caspase‐1 and IL‐1β in coronary arteriole endothelium of obese mice in immunofluorescence staining. HF‐RUN attenuated HFD‐dependent endothelial NO synthase (eNOS) reduction and thus increased NO production compared to HF‐SED. HFD elevated intracellular superoxide production in coronary arterioles while voluntary running ameliorated oxidative stress. Our findings provide the first evidence that voluntary running attenuates endothelial NLRP3 inflammasome activation in coronary arterioles of HFD feeding mice. Results further suggest that voluntary running improves obesity‐induced vascular dysfunction by preserved NO bioavailability via restored expression of eNOS and reduced oxidative stress.

Aerobic exercise regulates FGF21 and NLRP3 inflammasome-mediated pyroptosis and inhibits atherosclerosis in mice

“…Studies have shown that exercise can reduce cardiac oxidative stress and NLRP3 inflammasome expression in ApoE -/- mice [ 37 ]. Lee et al [ 47 ] found that exercise training could reduce the upregulated expression of NLRP3 and its downstream cascade factors in an obese mouse model. In a diabetic mouse model, exercise restored endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production by reducing NLRP3 expression, thereby eliminating downstream products of NLRP3 activation [ 48 ].…”

Severe COVID-19: NLRP3 Inflammasome Dysregulated

“…Elderly patients having an “inflammaging,” a low grade inflammation associated with NLRP3 inflammasome priming and activation and weaker inhibition ( 24 ) and, obese patients with a metainflammation ( 25 ) resulting in a higher base activity of NLRP3 ( 26 , 27 ). An enhanced exposure to DAMPs and NLRP3 inflammasome activation can affect immune fitness and is the result of a complex interplay where genetics [SNPs in NLRP3 ( 28 )] and also lifestyle factors [such as exercise, reduce NLRP3 activation ( 29 ), certain diets, block or stimulate NLRP3 activation ( 30 , 31 ) and, air pollution, induces NLRP3 activation ( 32 )] are interconnected.…”

Thermal dysregulation in patients with multiple sclerosis during SARS-CoV-2 infection. The potential therapeutic role of exercise

“…Plasma levels of adiponectin (APN) are increased by regular physical exercise (Saeidi et al, 2020; Zouhal et al 2021). APN binds to adiponectin receptor 1 (AdipR1) in endothelial cells, mitigating the induction of inflammasomes, especially NLPR3, whose signals include activation of caspase-1 and IL-1β ( Du et al, 2016 ; Hui et al, 2012 ; Lee et al, 2020 ; Lee et al, 2018 ; Lee et al, 2011 ). Downregulated inflammasomes attenuate ROS production in endothelial cells.…”