NLRP3 Inflammasome Promotes Myocardial Remodeling During Diet-Induced Obesity

Abstract

Background: Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1β and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations. Methods and Results: WT, Nlrp3 −/− , and ASC −/− ( Pycard −/− ) male mice were exposed to high fat diet (HFD; 60 cal% fat) or control diet for 52 weeks. Cardiac structure and function were evaluated by echocardiography and magnetic resonance imaging, respectively. Whereas, NLRP3 and ASC deficiency did not affect the cardiac hypertrophic response to obesity, it was preventive against left ventricle concentric remodeling and impairment of diastolic function. Furthermore, whereas NLRP3 and ASC deficiency attenuated systemic inflammation in HFD fed mice; long-term HFD did not induce significant cardiac fibrosis or inflammation, suggesting that the beneficial effects of NLRP3 inflammasome deficiency on myocardial remodeling at least partly reflect systemic mechanisms. Nlrp3 and ASC ( Pycard ) deficient mice were also protected against obesity-induced systemic metabolic dysregulation, as well as lipid accumulation and impaired insulin signaling in hepatic and cardiac tissues. Conclusions: Our data indicate that the NLRP3 inflammasome modulates cardiac concentric remodeling in obesity through effects on systemic inflammation and metabolic disturbances, with effect on insulin signaling as a potential mediator within the myocardium.

RETRACTED: Sirtuin1 Role in the Melatonin Protective Effects Against Obesity-Related Heart Injury

“…In the present study, we observed that the NLRP3 inflammosame, which plays an important role in the development of obesityrelated cardiac dysfunction and remodeling (Sokolova et al, 2019), was either absent or only very weakly expressed in the cardiomyocytes of lean mice (Figure 4A), whereas ob/ob mice showed moderate expression of this pro-inflammatory marker in the cytoplasm of cardiomyocytes (Figure 4B). Interestingly, NLRP3 was significantly suppressed (absent/very weak expression) in ob/ob mice supplemented with melatonin ( Figure 4C).…”

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

“…Furthermore, a reduction in the secretion of insulin-sensitive adipokines accompanied by oversecretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) is closely related to the etiology of various metabolic conditions. Other studies also point to the participation of NLRP3 in obesity because of its overexpression in AT [11,[69][70][71][72][73]. Moreover, the results of studies on mouse models of obesity are consistent with this observation [74,75].…”

NLRP3 inflammasome deficiency attenuates metabolic disturbances involving alterations in the gut microbial profile in mice exposed to high fat diet

“…However, when investigated in the LV tissue, IHC revealed no difference in the levels of ceramide between the genotypes. We have previously described the lack of both myocardial inflammation and fibrosis in our model of NLRP3 deficiency on HFD 22 compared to others 44,45 , and it is tempting to hypothesize that this at least partly could be due to differences in cardiac ceramide accumulation. Thus, whereas our findings support a link between NLRP3-driven inflammation and ceramide signaling systemically, the role of these pathways within the myocardium could be questioned.…”