Heart Center Freiburg University, Department of Cardiology and Angiology, Freiburg, Germany.
Heart Center Freiburg University, Department of Cardiology and Angiology, Freiburg, Germany; Departamento de Ciencias Básicas, Universidad Nacional de Luján, CONICET, Luján, Buenos Aires, Argentina.
J Mol Cell Cardiol. 2019 Aug;133:138-147. doi: 10.1016/j.yjmcc.2019.06.008. Epub 2019 Jun 13.
Sepsis-induced cardiomyopathy contributes to the high mortality of septic shock in critically ill patients. Since the underlying mechanisms are incompletely understood, we hypothesized that sepsis-induced impairment of sirtuin 3 (SIRT3) activity contributes to the development of septic cardiomyopathy.
Treatment of mice with lipopolysaccharide (LPS) for 6 h resulted in myocardial NAD depletion and increased mitochondrial protein acetylation, indicating impaired myocardial SIRT3 activity due to NAD depletion. LPS treatment also resulted in impaired cardiac output in isolated working hearts, indicating endotoxemia-induced cardiomyopathy. Maintaining normal myocardial NAD levels in LPS-treated mice by Poly(ADP-ribose)polymerase 1 (PARP1) deletion prevented cardiac dysfunction, whereas additional SIRT3 deficiency blunted this beneficial effect, indicating that impaired SIRT3 activity contributes to cardiac dysfunction in endotoxemia. Measurements of mitochondrial ATP synthesis suggest that LPS-induced contractile dysfunction may result from cardiac energy depletion due to impaired SIRT3 activity. Pharmacological inhibition of mitochondrial calpains using MDL28170 normalized LPS-induced cleavage of the ATP5A1 subunit of ATP synthase and normalized contractile dysfunction, suggesting that cardiac energy depletion may result from calpain-mediated cleavage of ATP5A1. These beneficial effects were completely blunted by SIRT3 deficiency. Finally, a gene set enrichment analysis of hearts of patients with septic, ischemic or dilated cardiomyopathy revealed a sepsis-specific suppression of SIRT3 deacetylation targets, including ATP5A1, indicating a functional relevance of SIRT3-dependent pathways in human sepsis.
Impaired SIRT3 activity may mediate cardiac dysfunction in endotoxemia by facilitating calpain-mediated disruption of ATP synthesis, suggesting SIRT3 activation as a potential therapeutic strategy to treat septic cardiomyopathy.
脓毒症诱导的心肌病导致重症患者感染性休克的死亡率居高不下。由于潜在的机制尚未完全阐明，我们假设脓毒症诱导的沉默调节蛋白 3（SIRT3）活性受损会导致脓毒性心肌病的发生。
用脂多糖（LPS）处理小鼠 6 小时会导致心肌 NAD 耗竭和线粒体蛋白乙酰化增加，表明由于 NAD 耗竭导致心肌 SIRT3 活性受损。LPS 处理还导致分离工作心脏的心输出量受损，表明内毒素血症诱导的心肌病。通过聚（ADP-核糖）聚合酶 1（PARP1）缺失使 LPS 处理的小鼠保持正常的心肌 NAD 水平可防止心脏功能障碍，而额外的 SIRT3 缺乏则削弱了这种有益作用，表明 SIRT3 活性受损会导致内毒素血症中的心脏功能障碍。线粒体 ATP 合成的测量表明，LPS 诱导的收缩功能障碍可能是由于 SIRT3 活性受损导致的心脏能量耗竭引起的。使用 MDL28170 抑制线粒体钙蛋白酶可使 LPS 诱导的 ATP 合酶 ATP5A1 亚基的切割正常化，并使收缩功能障碍正常化，表明心脏能量耗竭可能是钙蛋白酶介导的 ATP5A1 切割所致。这些有益作用完全被 SIRT3 缺乏所阻断。最后，对脓毒症、缺血性或扩张型心肌病患者心脏的基因集富集分析显示，SIRT3 去乙酰化靶标在脓毒症中特异性受到抑制，包括 ATP5A1，表明 SIRT3 依赖性途径在人类脓毒症中具有功能相关性。
SIRT3 活性受损可能通过促进钙蛋白酶介导的 ATP 合成破坏介导心脏功能障碍，提示 SIRT3 激活可能是治疗脓毒性心肌病的潜在治疗策略。
