Effects of Exercise on Epigenetic Pathways in Persons with Heart Failure Öffentlichkeit
Butts, Brittany (2016)
Published
Abstract
Introduction: Inflammation contributes to heart failure (HF) progression and interleukin (IL)-1 cytokines IL-1β and IL-18 are implicated in this process. The adaptor protein ASC (apoptosis associated speck-like protein containing a caspase recruitment domain) is necessary for inflammasome activation of IL-1β and IL-18. Lower ASC methylation is associated with worse outcomes in HF. The purpose of this study was to examine the effects of exercise on changes in ASC methylation and activation of interleukin-1 family cytokines IL-1β and IL-18 in persons with HF.
Methods: Participants (N=54) were randomized to receive exercise intervention (n=38) or attention control (n=16) for 3 months and were followed for an additional 3 months post-intervention. Blood samples for measures of percent methylation of the ASC gene, plasma IL-1β, IL-18, and ASC mRNA were obtained at baseline, 3 months, and 6 months.
Results: ASC methylation was higher in the exercise group as compared to control at 3 months (6.10±0.5% vs. 5.80±0.4%; p=.04) and 6 months (6.07±0.4 vs. 5.82±0.4; p=.04). Plasma IL-1β was lower in the exercise group at 3 months (1.43±0.5 pg/mL vs. 2.09±1.3 pg/mL; p=.02) and 6 months (1.49±0.5 pg/mL vs. 2.13±1.4 pg/mL; p=.004). In the exercise group, ASC methylation was higher at 3 months as compared to baseline (p=.009), and IL-1β was lower than baseline at both 3 (p<.001) and 6 months (p=.04). ASC mRNA expression was negatively associated with ASC methylation at baseline (r=-.97, p=.001), 3 months (r=-.90, p=.001), and 6 months (r=-.81, p=.001). ASC mRNA was lower than baseline at 3 months (p=.004) and 6 months (p=.002) among those in the exercise group. Significant group differences in change scores from baseline to 3 months were found for IL-1β (t=3.73, p=.001) and ASC methylation (t=-2.71, p=.01).
Conclusions: Exercise was related to increased mean percent ASC methylation and decreased IL-1β and ASC mRNA gene expression in HF. Epigenetic regulation of ASC may be a biological mechanism by which exercise can promote better outcomes in HF. Further research examining mechanisms of change can lead to improved understanding of physiological adaptations and more precise prediction of adverse outcomes in persons with HF.
Table of Contents
Chapter I: Introduction. 1
Figure 1.1 Conceptual Framework. 5
Table 1.1 Study Variables, Measures, and Time of Evaluation. 21
Table 1.2 Primers and PCR Conditions for ASC Methylation Analysis. 23
Table 1.3 Primers for qRT-PCR. 24
Table 1.4 Intervention Group Schedules. 26
Table 1.5 Aerobic Exercise Progression. 27
Chapter II: The Importance of NLRP3 Inflammasome in Heart Failure. 51
Figure 2.1 The NLRP3 Inflammasome. 79
Figure 2.2 Proposed Pathway of Epigenetic Regulation of the Inflammasome in Heart Failure. 80
Chapter III: ASC Methylation and Interleukin-1β Are Associated with Aerobic Capacity in Heart Failure. 81
Table 3.1 Demographic and Clinical Characteristics. 111
Table 3.2 Physical Measures by Gender. 112
Table 3.3 ASC and Cytokines. 113
Table 3.4 Multivariate Analysis of Predictors of Aerobic Capacity. 114
Chapter IV: Effects of an Exercise Intervention on ASC Methylation and IL-1 Cytokines in Persons with Heart Failure. 116
Table 4.1 Real-Time PCR Primers. 151
Table 4.2 Baseline Characteristics for the Total Sample and by Group. 152
Table 4.3 Mean Percent ASC Methylation, IL-1β, IL-18, and TNFα by Group. 154
Table 4.4 Multilevel Modeling for Entire Sample. 155
Table 4.5 Multilevel Modeling for Exercise Group Only. 156
Figure 4.1 Proposed Relationships Related to Inflammatory Changes after Exercise in Persons with Heart Failure. 157
Figure 4.2 Changes in Mean Percent ASC Methylation, IL-1β, IL-18, and TNFα over Time and by Group. 159
Figure 4.3 Mean ASC, IL-18 and iNOS RNA Expression by Group over Time. 161
Chapter V: Conclusion. 163
Figure 5.1 Association Between ASC Methylation, ASC Expression, and Cytokine Expression. 165
Figure 5.2 Increased ASC Methylation Has a Mediating Effect on Interleukin-1β. 170
Appendix A: Study Documents
Study Consent Form
Study Laboratory Approval Form
Appendix B: Permissions
Permission for Chapter II: The Importance of NLRP3 Inflammasome in Heart Failure
Permission for use of Figure 5.1
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