Abstract
Pulmonary arterial hypertension (PAH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PAH patients remains low. There is thus an important need to identify novel genes that are commonly dysregulated in PAH of various etiologies and could be used as biomarkers and/or therapeutic targets. In this study, we performed comparative transcriptome analysis of five mammalian PAH datasets downloaded from a public database. We identified 228 differentially expressed genes (DEGs) from a rat PAH model caused by inhibition of vascular endothelial growth factor receptor under hypoxic conditions, 379 DEGs from a mouse PAH model associated with systemic sclerosis, 850 DEGs from a mouse PAH model associated with schistosomiasis, 1598 DEGs from one cohort of human PAH patients, and 4260 DEGs from a second cohort of human PAH patients. Gene-by-gene comparison identified four genes that were differentially upregulated or downregulated in parallel in all five sets of DEGs. Expression of coiled-coil domain containing 80 (CCDC80) and anterior gradient two genes was significantly increased in the five datasets, whereas expression of SMAD family member six and granzyme A was significantly decreased. Weighted gene co-expression network analysis revealed a connection between CCDC80 and collagen type I alpha 1 (COL1A1) expression. To validate the function of CCDC80 in vivo, we knocked out ccdc80 in zebrafish using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. In vivo imaging of zebrafish expressing a fluorescent protein in endothelial cells showed that ccdc80 deletion significantly increased the diameter of the ventral artery, a vessel supplying blood to the gills. We also demonstrated that expression of col1a1 and endothelin-1 mRNA was significantly decreased in the ccdc80-knockout zebrafish. Finally, we examined Ccdc80 immunoreactivity in a rat PAHmodel and found increased expression in the hypertrophied media and adventitia of the pre-acinar pulmonary arteries (PAs) and in the thickened intima, media, and adventitia of the obstructed intra-acinar PAs. These results suggest that increased expression of CCDC80 may be involved in the pathogenesis of PAH, potentially by modulating the expression of endothelin-1 and COL1A1.
Highlights
Pulmonary arterial hypertension is a progressive disease characterized by increased pulmonary vascular resistance due to vasoconstriction and remodeling
These include data derived from two cohorts of human patients (Mura et al, 2012; Zhao Y. et al, 2014; Zhao Y.D. et al, 2014); a rat PAH model caused by treatment with the vascular endothelial growth factor receptor inhibitor SU5416 under conditions of hypoxia (Moreno-Vinasco et al, 2008); a mouse PAH model caused by overexpression of Fra-2 (Biasin et al, 2014), a causative gene for systemic sclerosis; a mouse PAH model caused by schistosomiasis (Graham et al, 2013); a rat model caused by left heart disease (Hoffmann et al, 2011); a rat model caused by Pneumocystis infection (Swain et al, 2014); and a mouse PAH model caused by deletion of cavin-1 (Swärd et al, 2013)
We demonstrated that expression of coiled-coil domain containing 80 (CCDC80), SMAD family member 6 (SMAD6), anterior gradient 2 (AGR2), and granzyme A (GZMA) was significantly dysregulated in two cohorts of human PAH patients (Mura et al, 2012; Zhao Y. et al, 2014; Zhao Y.D. et al, 2014) and in three rodent PAH models caused by: (i) treatment with a VEGF receptor inhibitor under conditions of hypoxia (Moreno-Vinasco et al, 2008); (ii) overexpression of Fra2, a causative gene for systemic sclerosis (Biasin et al, 2014); and (iii) schistosomiasis (Graham et al, 2013)
Summary
Pulmonary arterial hypertension is a progressive disease characterized by increased pulmonary vascular resistance due to vasoconstriction and remodeling (reviewed in Pullamsetti et al, 2014; McLaughlin et al, 2015). A number of transcriptome analyses of PAH patients and PAH animal models have been performed and the data have been deposited in a public database (Barrett et al, 2009) These include data derived from two cohorts of human patients (Mura et al, 2012; Zhao Y. et al, 2014; Zhao Y.D. et al, 2014); a rat PAH model caused by treatment with the vascular endothelial growth factor receptor inhibitor SU5416 under conditions of hypoxia (Moreno-Vinasco et al, 2008); a mouse PAH model caused by overexpression of Fra-2 (Biasin et al, 2014), a causative gene for systemic sclerosis; a mouse PAH model caused by schistosomiasis (Graham et al, 2013); a rat model caused by left heart disease (Hoffmann et al, 2011); a rat model caused by Pneumocystis infection (Swain et al, 2014); and a mouse PAH model caused by deletion of cavin-1 (Swärd et al, 2013).
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