Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: A physiological and gene expression-based approach
Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: A physiological and gene expression-based approach
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DOI：
10.1097/ccm.0b013e3181ce4e50
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发表时间：
2010-03-01
影响因子：
8.8
通讯作者：
Parker, Thomas G.
中科院分区：
文献类型：
--
作者：
dos Santos, Claudia C.;Gattas, David J.;Parker, Thomas G.
背景：一氧化氮产生增加和线粒体功能改变与脓毒症引起的心功能不全有关。脓毒症中心肌抑制的分子机制和一氧化氮在此过程中的作用还不完全清楚。目的：在临床相关小鼠模型中评估脓毒症诱导的心肌抑制相关的转录谱，并特别检验关键转录变化依赖于诱导型一氧化氮合酶的假设。设计：实验室研究。设置：C57/BL 6野生型和同源B6 129 P2-Nos 2 tm 1 Lau/J（iNOS（-/-））小鼠。干预：通过盲肠结扎和穿孔诱导多微生物脓毒症48小时后评估心肌功能。测量和结果：我们比较了C57/BL 6野生型小鼠和同系B6 129 P2-Nos 2 tm 1 Lau/J同窝小鼠在盲肠结扎和穿孔诱导的多微生物脓毒症48小时后的心肌转录谱。通过基因集富集分析对22，690个表达的序列标签进行的分析表明，诱导型一氧化氮合酶-/-未能下调关键的生物能量和代谢相关基因，包括过氧化物酶体增殖物激活受体γ共激活因子1的基因。生物信息学分析确定了一个惊人的一致性，在下调增殖物激活受体γ共激活因子1相关的转录因子的转录活性，导致脓毒症相关的心肌重塑所示的收缩蛋白肌球蛋白重链表达的亚型转换。在诱导型一氧化氮合酶-/-缺陷小鼠，收缩抑制是最小的，和转录开关是absent.Conclusions：代谢和肌球蛋白亚型基因表达开关在脓毒症诱导的心肌抑制是诱导型一氧化氮合酶依赖。此外，我们认为，有利于胎儿亚型的收缩相关蛋白质的表达的分子开关与增殖物激活受体γ辅激活因子1和相关转录因子的调节诱导型一氧化氮合酶依赖的方式。(Crit Care Med 2010; 38：894 - 902）
Background: Increased nitric oxide production and altered mitochondrial function have been implicated in sepsis-induced cardiac dysfunction. The molecular mechanisms underlying myocardial depression in sepsis and the contribution of nitric oxide in this process however, are incompletely understood.Objectives: To assess the transcriptional profile associated with sepsis-induced myocardial depression in a clinically relevant mouse model, and specifically test the hypothesis that critical transcriptional changes are inducible nitric oxide synthase-dependent.Design: Laboratory investigation.Setting: University affiliated research laboratory.Subjects: C57/BL6 wild type and congenic B6 129P2-Nos2tm1Lau/J (iNOS(-/-)) mice.Interventions: Assessment of myocardial function after 48 hrs of induction of polymicrobial sepsis by caecal ligation and perforation.Measurements and Results: We compared the myocardial transcriptional profile in C57/BL6 wild type mice and congenic B6 129P2-Nos2tm1Lau/J litter mates after 48 hrs of polymicrobial sepsis induced by caecal ligation and perforation. Profiling of 22,690 expressed sequence tags by gene set enrichment analysis demonstrated that inducible nitric oxide synthase -/- failed to down regulate critical bioenergy and metabolism related genes including the gene for peroxisome proliferator-activated receptor gamma coactivator 1. Bioinformatics analysis identified a striking concordance in down regulation of transcriptional activity of proliferator-activated receptor gamma coactivator 1-related transcription factors resulting in sepsis associated myocardial remodeling as shown by isoform switching in the expression of contractile protein myosin heavy chain. In inducible nitric oxide synthase -/- deficient mice, contractile depression was minimal, and the transcriptional switch was absent.Conclusions: Metabolic and myosin isoform gene expression switch in sepsis-induced myocardial depression is inducible nitric oxide synthase-dependent. Furthermore, we suggest that the molecular switch favoring the expression of fetal isoforms of contraction related proteins is associated with regulation of proliferator-activated receptor gamma coactivator 1 and related transcription factors in an inducible nitric oxide synthase-dependent manner. (Crit Care Med 2010; 38: 894 -902)