ASC Methylation and Interleukin-1β Are Associated with Aerobic Capacity in Heart Failure

Abstract

Background Aerobic capacity, as measured by peak oxygen uptake (V̇O2), is one of the most powerful predictors of prognosis in heart failure (HF). Inflammation is a key factor contributing to alterations in aerobic capacity, and interleukin (IL)-1 cytokines are implicated in this process. The adaptor protein ASC is necessary for inflammasome activation of IL-1β and IL-18. ASC expression is controlled through epigenetic modification; lower ASC methylation is associated with worse outcomes in HF. The purpose of this study is to examine the relationships between ASC methylation, IL-1β, and IL-18 with peak V̇O2 in persons with HF. Methods This study examined the relationship between ASC methylation, IL-1β, and IL-18 with peak V̇O2 in 54 stable outpatients with HF. All participants were NYHA class II or III, not engaged in an exercise program, and physically able to complete an exercise treadmill test. Results Mean peak V̇O2 was 16.68 ± 4.7 ml/kg/min. Peak V̇O2was positively associated with mean percent ASC methylation (r=.47, p=.001) and negatively associated with IL-1β (r=-.38, p=.007). Multiple linear regression models demonstrated that peak V̇O2 increased by 2.30 ml/kg/min for every 1% increase in ASC methylation and decreased by 1.91 ml/kg/min for every 1 pg/mL increase in plasma IL-1β. Conclusions Mean percent ASC methylation and plasma IL-1β levels are associated with clinically meaningful differences in peak V̇O2 in persons with HF. Inflammasome activation may play a mechanistic role in determining aerobic capacity. ASC methylation is a potentially modifiable mechanism for reducing the inflammatory response, thereby improving aerobic capacity in HF.

Low-grade chronic inflammation is attenuated by exercise training in obese adults through down-regulation of ASC gene in peripheral blood: a pilot study

“…Other studies have demonstrated hypermethylation of the ASC gene in heart failure patients and in older individuals after exercise, and in turn, methylation was related to decreased expression of ASC and IL-1 family. Therefore, exercise may play an important role in the epigenetic modification of the ASC gene [8,9,17,18]. Although in this study we did not measure IL-1β or IL-18 expression, we quantified both cytokines; however, no significant differences were found probably because our study population did not have another metabolic disease.…”

Association Analysis of NLRP3 Inflammation-Related Gene Promotor Methylation as Well as Mediating Effects on T2DM and Vascular Complications in a Southern Han Chinese Population

“…Human embryonic kidney cells infected with Mycobacterium tuberculosis H37Rv reduced NLRP3 promoter region methylation and then activated NLRP3 inflammation, resulting in upregulation of the RNA level of NLRP3 and IL-1β ( 41 ). The VO2 max of heart failure patients was positively related to the level of the ASC average methylation level and negatively correlated with the plasma concentration of IL-1β ( 42 ). These studies indirectly supported our observations of relationships between NLRP3, AIM2, and ASC methylation level changes and inflammation.…”

Low-grade chronic inflammation is attenuated by exercise training in obese adults through down-regulation of ASC gene in peripheral blood: a pilot study

“…Other studies have demonstrated hypermethylation of the ASC gene in heart failure patients and in older individuals after exercise, and in turn, methylation was related to decreased expression of ASC and IL-1 family. Therefore, exercise may play an important role in the epigenetic modi cation of the ASC gene [8,9,17,18]. Although in this study we did not measure IL-1β or IL-18 expression, we quanti ed both cytokines; however, no signi cant differences were found probably because our study population did not have another metabolic disease.…”