Transcriptomics of High Altitude Disease in Holstein Calves

High-altitude disease is an economically important problem in beef and dairy cattle at high altitudes (>1800 m). The disease is partly associated with vascular inflammation of the pulmonary artery due to hypoxia, resulting in pulmonary hypertension that can lead to congestive heart failure. Earlier studies have suggested that high-altitude disease is a heritable disease; however, minimal information exists on the identity of the genes involved. Recent experimental evidence suggests that innate activation of fibroblasts may play a central role in the initiation and perpetuation of the inflammatory tissue responses. To develop a better understanding of the etiology of this disease, we used RNA-Seq to examine the transcriptome of fibroblasts derived from cultures of healthy Control (n=6) and Hypertensive (n=6) neonatal Holstein calves. Using t-tests, 1012 differential expressed genes were identified between the two groups (P<0.01, fold change > 2). Among the differentially expressed genes, CTBP1 (C-terminal binding protein 1) and CTBP2 genes were highly expressed (P<0.01) in Hypertensive calves. These genes represent markers of cell proliferation and inflammation processes. Also, several factors involved in monocyte recruitment, retention and activation were overexpressed in hypertensive activated fibroblasts (CXCL12, HGF, IL6, IL33 and VCAM1 genes; P<0.05). A high proportion of genes involved in glycolysis/gluconeogenesis, TCA cycle and insulin signaling pathways were overexpressed in Hypertensive calves (P<0.01). These results suggest potential target genes with important roles in metabolic changes of pulmonary hypertensive fibroblasts may involve changes in glucose and lipid metabolism. These findings open a new window to understand the genetic architecture associated with high-altitude disease in cattle.