PURPOSE: The aim of this study was to obtain endoarterial biopsy samples in a surgical porcine model of PAH in order to construct a microarray-based map of changes in gene expression in the arterial wall during PAH progression.
METHODS: Pigs underwent surgical anastomosis of the left pulmonary artery to the descending aorta, resulting in left PAH of at least ½ systemic level. Endovascular samples were obtained from 2–3 mm arteries with an endoarterial biopsy catheter at baseline (prior to surgery), and from the hypertensive left lung 21 and 60 days after surgery. RNA, isolated from biopsy samples, was loaded into an Affymetrix GeneChip Porcine Whole Genome Array. Gene expression level differences between samples from baseline, 21- and 60-day time-points were then analyzed. Gene expression changes relative to baseline were then used to identify the expression of dysregulated genes previously described to be associated with PAH as well as new upregulated genes, for which there are known inhibitors, in order to identify existing drugs which could potentially be used to treat or prevent PAH.
RESULTS: Data were obtained from 4 animals. The validity of the model was confirmed by examining the expression changes for selected genes previously found to be dysregulated in PAH, such as EDN1, TIE2, TGFB2, 5-HT2B, BIRC5, ANG2 which were upregulated, eNOS3, iNOS, APOE, PPARG which were downregulated. Genes with known inhibitors currently in use or under investigation for PAH, such as EDNRB, HTR2B, PDGFRA, HMGCR, KCNB1 were also found to be upregulated in our model. Interestingly, genes for which there are known inhibitors, but no previous association with PAH such as C5, HPSE, MAOB, HDAC2, CXCR4, IFNAR2, PREP, RRM1, POLG, RARB, HPRT1, CDK7, ADORA3, KCNJ2, CCR5, LTB4R2, MAOA, TLR8 were also found to be upregulated. Gene dysregulation varied between time points.
CONCLUSION: Endoarterial biopsy provides a new method to assess pulmonary vascular gene expression and identify novel PAH applications for existing drugs.
CLINICAL IMPLICATIONS: The detection of stage-specific variation in gene expression could lead to individualized pharmacogenomics.
DISCLOSURE: David Mann, Shareholder Shareholder, Vascular BioSciences; Employee Employee, Vascular BioSciences; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Endoarterial biopsy catheter