PSI-10 Pathway analyses revealed up-regulation of calcium-dependent genes in the cardiac right ventricle of Angus steers fed at high altitude

Pulmonary hypertension (PH) and subsequent right heart failure is an economic burden for high altitude beef production systems. An indicator of PH is pulmonary arterial pressure (PAP), which has been used to improve tolerance of cattle to high altitude due to its moderate heritability (0.20 to 0.40). A key mediator of myocardial contraction and relaxation is intracellular signaling of calcium. We hypothesized that genes involved in calcium signaling pathways have a role in susceptibility of cattle to PH at high altitude. Right ventricle tissues were collected from Angus steers (age 12 to 14 months; live weight 387 ± 2.5 kg) fed and harvested at high altitude (2,170 m). Experimental groups consisted of low PAP, healthy (average 39 ± 0.2 mm Hg; n = 7) and high PAP, sick/symptomatic of potential heart failure (average 82 ± 2.9 mm Hg; n = 3) steers. Gene expression counts were estimated from RNA-sequence data and then analyzed with DESeq, resulting in 622 differentially expressed genes between experimental groups (Fold change > 2.0; P < 0.05), after a multiple testing correction with the Benjamini-Hochberg procedure. Ingenuity Pathway Analysis revealed the top disease and biological function as cardiovascular malformation represented by 134 of the differentially expressed genes (P < 0.01). The principal intra-pathway genes identified were TGFβ1, an upstream regulator of ventricular chamber hypertrophy and systolic dysfunction leading to heart failure, and EDN1, a vasoconstrictor with downstream regulatory effects on intracellular calcium availability. Two additional genes, FBLN7, a calcium-binding glycoprotein; and ANKRD2, which interacts with calcium-dependent genes, represented the highest expression fold changes. These results support our hypothesis that calcium-dependent gene regulation appears to be influenced by PH (right ventricle malformation) in Angus steers fed at high altitude.