Role of Physical Activity in Inflammasome-mediated Vascular Endothelial Dysfunction in Obesity

Date

2019-12

Journal Title

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Abstract

Obesity contributes to the development of cardiovascular disease (CVD) which is a leading cause of mortality in the world. Endothelial dysfunction, the earliest event of CVD, is largely attributed to a complex interplay of nitric oxide (NO) production, oxidative stress, and inflammation. The proinflammatory cytokine interleukin-1β (IL-1β) is processed by nucleotide-binding oligomerization-domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome-mediated caspase-1 cleavage and is a crucial mechanism for vascular pathology in obesity. Physical activity is the first line of defense against obesity-associated vascular health problems since it has multiple protective properties operating through a myriad of physiological mechanisms. However, no study has reported whether physical activity affects NLRP3 inflammasome-associated vascular dysfunction in obesity, nor have any studies, to date, fully determined the underlying mechanisms responsible for the vascular health improvements in response to exercise. Also, considering that abnormal dilatory function in micro (resistance) vessels typically precedes those in macro (conduit) vessels, it is necessary to investigate the molecular adaptations to physical activity in both vascular beds in obesity. Thus, the purpose of this dissertation was to elucidate the underlying mechanism(s) by which physical activity ameliorates NLRP3 inflammasome-associated endothelial dysfunction in obesity. We hypothesized that physical activity would attenuate the obesity-induced inflammasome signaling responsible for endothelial dysfunction in the resistance and conduit vessels. To test our hypothesis, we used C57BL/6J male mice provided with high-fat diet (HFD) to develop diet-induced obese model simultaneously with voluntary running wheel to mimic natural physical activity in humans. We investigated the inflammasome signaling pathway, NO, and oxidative stress-associated molecular mechanisms in the resistance vessels (coronary arterioles) and conduit (aorta) vessels in obese mice. Also, we explored putative mechanisms of the inflammasome-related vascular dysfunction via adiponectin (APN)-adiponectin receptor 1 (AdipoR1) axis, a potential inhibitor of inflammasome, and tight junction adaptors zonula occludens-1 (ZO-1) and ZO-2, downstream target of the inflammasome responsible for endothelial dysfunction. We found that coronary arteriole and aorta from HFD mice exhibit decreases in NO production and increases in oxidative stress, however, these alterations are corrected by voluntary running. In both coronary arteries and aorta from obese mice, voluntary running attenuates obesity-induced increase of active caspase-1 and IL-1β representative indicators of NLRP3 inflammasome activation. Voluntary running restores APN-AdipoR1 contents and ZO-1/2 expression in endothelial cells of the obese aorta. Thus, this study demonstrates that physical activity is protective against the inflammasome-mediated vascular dysfunction in obesity through restoring NO production, APN-AdiopoR1, and ZO-1/2 expression, and decreasing oxidative stress and the inflammasome.

Description

Keywords

Physical exercise, Inflammation, Vascular dysfunction, Obesity

Citation

Portions of this document appear in: Lee, Jonghae, Yang Lee, Emily C. LaVoy, Michihisa Umetani, Junyoung Hong, and Yoonjung Park. "Physical activity protects NLRP 3 inflammasome‐associated coronary vascular dysfunction in obese mice." Physiological reports 6, no. 12 (2018): e13738. And in: Lee, Jonghae, Yang Lee, Emily C. LaVoy, Michihisa Umetani, Junyoung Hong, and Yoonjung Park. "Physical activity protects NLRP 3 inflammasome‐associated coronary vascular dysfunction in obese mice." Physiological reports 6, no. 12 (2018): e13738.