Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Influences of adenosine 2A receptor (A(2A)R) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A(2A)R-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A(2A)R-sensitive genes modified by A(2A)R 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, NF kappa B and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed -adrenergic, PKA and Ca2+ 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 A(2A)R KO, supporting inflammatory suppression via A(2A)R sensitive shifts in regulators of NF kappa B and JAK-STAT signalling (I kappa B zeta, I kappa B alpha, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate A(2A)Rs exert minor effects in un-stressed myocardium and selectively suppress NF kappa B and JAK-STAT signalling and cardiac injury without influencing cardiac depression in endotoxemia.