Abstract
The incidence of atherosclerosis (AS), a major contributor to cardiovascular disease, is steadily rising along with an increasingly older population worldwide. Pyroptosis, a form of inflammatory programmed cell death, determines the release of pro-inflammatory mediators by endothelial cells, smooth muscle cells, and atheroma-associated macrophages and foam cells, thereby playing a critical role in AS progression. Canonical pyroptosis is mediated by inflammasome formation, activation of caspase-1, and maturation and release of proinflammatory cytokines. Electrical stimulation (ES) is a noninvasive, safe therapy that has been shown to alleviate symptoms in several health conditions. Here, we investigated the anti-inflammatory and anti-pyroptotic effects of ES in human THP-1 macrophages treated with the dipeptidyl peptidase inhibitor Val-boroPro (VbP). We found that ES downregulated NOD-like receptor family protein 3 (NLRP3) inflammasome, ASC, and caspase-1 expression and abrogated the release of Interleukin-1β (IL-1β) and Interleukin-18 (IL-18), indicating effective pyroptosis inhibition. These changes were paralleled by a reduction in reactive oxygen species (ROS) production, reversal of VbP-induced sirtuin3 (Sirt3) downregulation, deacetylation of ATG5, and induction of autophagy. These findings suggest that ES may be a viable strategy to counteract pyroptosis-mediated inflammation in AS by raising Sirt3 to promote autophagy and inhibit ROS generation.
Highlights
Atherosclerosis (AS), a chronic inflammatory disease of the arterial wall characterized by gradual build-up of arterial plaque, is the main cause of cardiovascular disease (CVD) [1, 2]
We confirmed that the expression of NOD-like receptor family protein 1 (NLRP1), another inflammasome complex involved in pyroptosis, did not change significantly under the above conditions (Figure 1E and 1F)
After Electrical stimulation (ES) of THP-1 macrophages treated with VbP, the increase of Sirt3 expression accelerated the occurrence of autophagy and inhibited the production of reactive oxygen species (ROS) effectively, which inhibited the expression of NODlike receptor family protein 3 (NLRP3), resulting in ASC unable to recruit pro-caspase-1 and induce its own cleavage to form mature caspase-1, and the decrease of IL-18 and IL-1β expression (Figure 9)
Summary
Atherosclerosis (AS), a chronic inflammatory disease of the arterial wall characterized by gradual build-up of arterial plaque, is the main cause of cardiovascular disease (CVD) [1, 2]. Accumulating data indicates that pyroptosis, a highly inflammatory form of programmed cell death usually triggered in immune cells upon infection by intracellular pathogens, occurs in AS-associated macrophages and contributes importantly to plaque instability [7, 8]. NODlike receptor family protein 3 (NLRP3), the best characterized inflammasome type, is a crucial signaling node that controls caspase-1 mediated maturation of Interleukin-1β (IL-1β) and Interleukin-18 (IL-18) [14]. This is achieved by recruitment of the adapter protein ASC (apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain) to the NLRP3 complex, which results in cleavage of pro-caspase-1 into biologically active caspase-1 [15, 16]. Of relevance for CVD, it has been shown that vascular Sirt expression in humans decreases with age, and forced Sirt expression greatly improves graft integration after vein-graft stenting in rats [24]
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