Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore.
Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore.
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DOI：
10.33594/000000151
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Garcia-Rivas, Gerardo
中科院分区：
文献类型：
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作者：
Castillo, Elena C;Morales, Jose A;Garcia-Rivas, Gerardo
背景/目标：亲环素D（CypD）介导线粒体通透性转换孔（mPTP）开放，其导致线粒体功能障碍。CypD受其乙酰化/脱乙酰化状态的调节，其依赖于Sirtuin-3（SIRT 3）线粒体脱乙酰化酶。由于肥胖和代谢综合征降低SIRT 3活性和表达，我们检验了CypD过度乙酰化在这种病理生理状态下促进线粒体功能障碍的假设，这与心室功能障碍和心力衰竭有关。来自患有左心室心力衰竭的肥胖或正常体重患者的心肌组织样品，通过Western Blot（WB）处理SIRT 3的表达和乙酰化谱。此外，进行了由30%（w/v）蔗糖诱导的肥胖和代谢综合征的大鼠模型。WB分析用于确定SIRT 3、腺嘌呤核苷酸转运子（ANT）、CypD的线粒体表达水平和乙酰化谱，以及免疫沉淀以建立CypD的乙酰化水平。线粒体功能通过耗氧量分析和最大Ca 2+滞留能力进行评估。氧化应激进行了评估乌头酸酶活性，蛋白质羰基和硫醇基团content.RESULTS：SIRT 3的表达在活检的失败的人的心脏表现出46%的肥胖患者的表达水平相比，非肥胖患者（p=0.0219）。值得注意的是，体重指数与蛋白质乙酰化相关（0.627; p = 0.035），表明肥胖患者衰竭心脏的乙酰化特征部分由SIRT 3的减少介导，SIRT 3也与较高的BNP水平相关，表明更严重的心室功能障碍（-0.636; p = 0.043）。因此，肥胖大鼠表现出SIRT 3线粒体表达降低22%，伴随着高度乙酰化的线粒体谱，包括CypD。肥胖动物的心肌线粒体比controls.CONCLUSION：我们的研究结果表明，肥胖降低SIRT 3的表达和CypD的超乙酰化增加mPTP开放，这表明SIRT 3的激活可能是一个潜在的目标，以减少心室功能障碍和减缓心力衰竭的进展。
BACKGROUND/AIMS: Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure.METHODS: Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content.RESULTS: SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls.CONCLUSION: Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.