Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure.
Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure.
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DOI：
10.1016/j.cardfail.2015.12.004
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发表时间：
2016-05
影响因子：
6
通讯作者：
Butler J
中科院分区：
文献类型：
--
作者：
Butts B;Gary RA;Dunbar SB;Butler J
心衰（HF）与炎症有关，其特征是炎症小体的形成，炎症小体触发炎症细胞因子的成熟。ASC是炎性小体的重要组成部分，通过表观遗传修饰控制，这可能是心衰恶化的候选途径。本研究探讨了HF的炎性体途径以及ASC CpG甲基化与HF预后之间的关系。分析155例HF门诊患者（射血分数29.9±14.9）的存储样本，分析ASC基因外显子-1前的内含子区域7个CpG位点的%甲基化。ASC甲基化与ASC mRNA （r= - 0.33，P<.001）和蛋白（r= - 0.464，P<.001）呈负相关。ASC甲基化与射血分数（r= 0.85，P< 0.001）、生活质量（r= 0.83，P< 0.001）和6分钟步行测试（r= 0.59，P= 0.023）呈线性正相关，与抑郁（r= - 0.81，P< 0.001）和焦虑（r= - 0.75，P< 0.001）呈线性负相关。较高的ASC甲基化与较低的临床事件风险相关（HR 0.16，P= 0.025），而较高的蛋白质（HR=1.78，P= 0.045）和mRNA表达（HR=1.18，P= 0.05）与较高的风险相关。ASC内含子区域CpG位点甲基化的增加与HF预后的改善有关。相关的ASC表达减少暗示这种炎症介质可能是HF结果的驱动因素，并可能代表治疗靶点。
Heart failure (HF) is associated with inflammation characterized by the formation the inflammasome, which triggers maturation of inflammatory cytokines. ASC, a vital component of the inflammasome, is controlled through epigenetic modification, which may be a candidate pathway for worsening HF. This study examined the inflammasome pathway in HF and the relationships between ASC CpG methylation and outcomes in HF. Stored samples from 155 HF outpatients (ejection fraction 29.9±14.9) were analyzed for % methylation of seven CpG sites in the intron region preceding exon-1 of the ASC gene. ASC methylation was inversely related to ASC mRNA (r=−.33,P<.001) and protein (r=−.464,P<.001). ASC methylation had a positive linear relationship with ejection fraction (r=.85,P<.001), quality of life (r=.83,P<.001), and six-minute walk test (r=.59,P=.023), and a negative linear relationship with depression (r=−.81,P<.001) and anxiety (r=−.75,P<.001). Higher ASC methylation was associated with a lower risk for clinical events (HR 0.16,P=.025), while higher protein (HR=1.78,P=.045) and mRNA expression (HR=1.18,P=.05) were associated with a greater risk. Increased methylation of CpG sites in the intron region of ASC is associated with improved outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes and may represent a therapeutic target.