Ashton Kevin J, Reichelt Melissa E, Mustafa S Jamal, Teng Bunyen, Ledent Catherine, Delbridge Lea M D, Hofmann Polly A, Morrison R Ray, Headrick John P
Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia.
School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.
Purinergic Signal. 2017 Mar;13(1):27-49. doi: 10.1007/s11302-016-9536-1. Epub 2016 Sep 30.
Influences of adenosine 2A receptor (AR) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify AR-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 AR-sensitive genes modified by AR KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2. Few canonical paths were impacted, with altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) implicating modified G protein/cAMP/PKA and cGMP/NOS signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for 24 h modified >4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and Cxcl1 (+89) and the most repressed are Car3 (-38); Adipoq (-17); Atgrl1/Aplnr (-14); H19 (-11) and Itga8 (-8). Canonical responses centred on inflammation, immunity, cell death and remodelling, with pronounced amplification of toll-like receptor (TLR) and underlying JAK-STAT, NFκB and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed ß-adrenergic, PKA and Ca signalling, electromechanical and mitochondrial function (and major shifts in transcripts impacting function/injury including Lcn2, S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, Igf1 and Aplnr repression). Endotoxemic responses were selectively modified by AR KO, supporting inflammatory suppression via AR sensitive shifts in regulators of NFκB and JAK-STAT signalling (IκBζ, IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate ARs exert minor effects in un-stressed myocardium and selectively suppress NFκB and JAK-STAT signalling and cardiac injury without influencing cardiac depression in endotoxemia.
腺苷2A受体（AR）活性对心脏转录组和内毒素血症性心肌炎发生的影响尚不清楚。我们应用转录组分析（39K Affymetrix芯片）来鉴定在健康和内毒素血症心脏中通过受体敲除（KO）揭示的AR敏感分子。基线心脏功能未改变，只有37个AR敏感基因因AR敲除而发生改变（变化≥1.2倍，错误发现率<5%）；诱导程度最高的五个基因是Mtr、Ppbp、Chac1、Ctsk和Cnpy2，抑制程度最高的五个基因是Hp、Yipf4、Acta1、Cidec和Map3k2。很少有经典通路受到影响，Gnb1、Prkar2b、Pde3b和Map3k2（以及其他基因）的改变涉及G蛋白/cAMP/PKA和cGMP/NOS信号传导的改变。用脂多糖（LPS；20mg/kg）刺激24小时可使野生型（WT）心肌中的>4100个转录本发生改变（变化≥1.5倍，错误发现率<1%）；诱导程度最高的是Lcn2（+590）；Saa3（+516）；Serpina3n（+122）；Cxcl9（+101）和Cxcl1（+89），抑制程度最高的是Car3（-38）；Adipoq（-17）；Atgrl1/Aplnr（-14）；H19（-11）和Itga8（-8）。经典反应集中在炎症、免疫、细胞死亡和重塑方面，Toll样受体（TLR）以及潜在的JAK-STAT、NFκB和MAPK通路有明显放大，还有一个“心脏抑制”谱，包括β-肾上腺素能、PKA和Ca信号传导、机电和线粒体功能受到抑制（以及影响功能/损伤的转录本发生重大变化，包括Lcn2、S100a8/S100a9、Icam1/Vcam和Nox2的诱导，以及Adipoq、Igf1和Aplnr的抑制）。AR敲除选择性地改变了内毒素血症反应，通过AR敏感地改变NFκB和JAK-STAT信号传导的调节因子（IκBζ、IκBα、STAT1、CDKN1a和RRAS2）来支持炎症抑制，而不影响心脏抑制基因谱。数据表明，AR在未受应激的心肌中发挥较小作用，并选择性地抑制NFκB和JAK-STAT信号传导以及心脏损伤，而不影响内毒素血症时的心脏抑制。
