Anne-Marie Koop

2 39 Figure 5 .Comparison of PAB- and PAB+CF at 5 weeks. PAB- and PAB+CF were significantly different at 5 weeks with regard to run distance (A, percentage change in run distance at 5 weeks vs. baseline), RV stroke volume (B), TAPSE (C) and cardiac index (D, in mL/min/g bodyweight). Cardiac index was stable in all groups at termination vs. 5 weeks (E). Mean±SEM. Arrows indicate p<0.05 between respective groups. PAB(11w)= PAB rats terminated at 11wks, TAPSE= tricuspid annular plane systolic excursion. Changes in gene expression following PAB Because no evident culprit has yet been found in RVF, and the etiology of RVF is likely multifactorial, we performed transcriptome-wide expression profiling, to study pathways involved in RVF. PAB induced significant changes in expression of >3000 genes. 1,437 of these and 263 of the significantly regulated gene sets were present in both PAB- and PAB+CF ( figure 6 , supplemental table 1 ). As expected, up regulation in the common gene pattern predominantly involved cardiac/cellular growth, and multiple interwoven and well known signaling pathways (MAPK-ERK1/2, PI3K-Akt- NFkappaBeta-mTOR, Integrins, TGF- beta, endothelin etc.). Down regulation was seen in specific gene sets related to metabolism, for example down regulation of PPAR alpha signaling, intermediary enzymes in fatty acid metabolism, PGC1 alpha signaling, mitochondrial gene expression and oxidative phosphorylation ( figure 6 , supplemental table 1 ). Whereas genes involved in fatty acid metabolism were downregulated in rats subjected to pressure load, with and without clinical symptoms, genes involved in glycolysis and gluconeogenesis were specifically downregulated in rats with clinical right ventricular failure.