Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
Crit Care Med. 2010 Mar;38(3):894-902. doi: 10.1097/CCM.0b013e3181ce4e50.
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.
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.
Laboratory investigation.
University affiliated research laboratory.
C57/BL6 wild type and congenic B6 129P2-Nos2tm1Lau/J (iNOS) mice.
Assessment of myocardial function after 48 hrs of induction of polymicrobial sepsis by caecal ligation and perforation.
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.
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.
一氧化氮产量增加和线粒体功能改变与脓毒症引起的心功能障碍有关。然而，脓毒症引起的心肌抑制的分子机制以及一氧化氮在此过程中的作用尚不完全清楚。
在一种临床相关的小鼠模型中评估与脓毒症引起的心肌抑制相关的转录谱，并特别检验关键转录变化是诱导型一氧化氮合酶依赖性的假设。
实验室研究。
大学附属研究实验室。
C57/BL6 野生型和同基因 B6 129P2-Nos2tm1Lau/J（iNOS）小鼠。
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。
我们比较了 C57/BL6 野生型小鼠和同基因 B6 129P2-Nos2tm1Lau/J 同窝小鼠在盲肠结扎和穿孔诱导多微生物脓毒症 48 小时后的心肌转录谱。通过基因集富集分析对 22690 个表达序列标签进行分析表明，诱导型一氧化氮合酶缺失未能下调关键生物能和代谢相关基因，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。生物信息学分析表明，转录因子的转录活性明显下调，导致与脓毒症相关的心肌重构，这表现为收缩蛋白肌球蛋白重链表达的同工型转换。在诱导型一氧化氮合酶缺陷型小鼠中，收缩抑制最小，转录转换不存在。
脓毒症诱导的心肌抑制中的代谢和肌球蛋白同工型基因表达转换依赖于诱导型一氧化氮合酶。此外，我们提出，有利于收缩相关蛋白胎儿同工型表达的分子转换与以诱导型一氧化氮合酶依赖的方式调节过氧化物酶体增殖物激活受体γ共激活因子 1 和相关转录因子有关。
