Effects of Exercise on Epigenetic Pathways in Persons with Heart Failure Open Access

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

About this Dissertation

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School	Laney Graduate School
Department	Nursing
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nursing
Keyword	inflammation epigenetics exercise heart failure
Committee Chair / Thesis Advisor	Gary, Rebecca A, Emory University Dunbar, Sandra B, Emory University
Committee Members	Butler, Javed, Emory University Corwin, Elizabeth, Emory University

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