NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction

Abstract

The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

“…Meanwhile, our present data also revealed that the activation of NLRP3 inflammasome triggered by LPS and ATP induced the activation of autophagy in Caco-2 cells, which is consistent with the previous study showing that NLRP3 inflammasome activation could induce mitophagy/autophagy in peritoneal mesothelial cells [45]. On the contrary, several evidences illustrate that inhibiting NLRP3 inflammasome would trigger autophagy activation [46]. Hence, it is necessary to identify the precise relationship between NLRP3 inflammasome activation and autophagy activation.…”

NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice

“…mTOR is a serine‐threonine kinase that functions as an intracellular energy sensor whose genetic and pharmacological inhibition has been shown to extend life in a wide range of organisms (Cordero, Williams, & Ryffel, ; Wu et al, ). Since it is known that mTOR induces autophagy, the ablation of NLRP3 also showed, consistent with previous data showing the effect of inhibition of NLRP3 with other stressors, such as a hypercaloric diet, an increase in autophagy during aging (Pavillard et al, ). Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and the accumulation of misfolded proteins and dysfunctional mitochondria.…”

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

“…In fact, NLRP3‐deficient mice have been reported to exhibit significant protection from high fat diet‐induced metabolic syndrome, characterized by reduced sterile inflammation (i.e., a decrease in the frequency of effector T cell infiltrate in visceral adipose tissue), reduced adipocyte hypertrophy and liver steatosis, and preservation of pancreatic β‐cell mass that results in improved insulin sensitivity and glucose tolerance . A number of studies have now largely confirmed this pathogenic role for NLRP3 and ASC in obesity‐related disorders, such as insulin resistance and Type 2 diabetes, nonalcoholic steatohepatitis (NASH) and cardiovascular disease (e.g., atherosclerosis) …”