Transcriptome analysis of a dog model of congestive heart failure shows that collagen-related 2-oxoglutarate-dependent dioxygenases contribute to heart failure.

Fibrosis is an important pathological mechanism in heart failure (HF) and is associated with poor prognosis. We analyzed fibrosis in HF patients using transcriptomic data. Genes differentially expressed between normal control and congestive HF (CHF) dogs included P3H1, P3H2, P3H4, P4HA2, PLOD1 and PLOD3, which belong to the 2-oxoglutarate-dependent dioxygenases (2OGD) superfamily that stabilizes collagen during fibrosis. Quantitative polymerase chain reaction analysis demonstrated 2OGD gene expression was increased in CHF samples compared with normal left ventricle (LV) samples. 2OGD gene expression was repressed in angiotensin converting enzyme inhibitor-treated samples. These genes, activated the hydroxylation of proline or lysin residues of procollagen mediated by 2-oxoglutaric acid and O2, produce succinic acid and CO2. Metabolic analysis demonstrated the concentration of succinic acid was significantly increased in CHF samples compared with normal LV samples. Fibrosis was induced in human cardiac fibroblasts by TGF-ß1 treatment. After treatment, the gene and protein expressions of 2OGD, the concentration of succinic acid, and the oxygen consumption rate were increased compared with no treatment. This is the first study to show that collagen-related 2OGD genes contribute to HF during the induction of fibrosis and might be potential therapeutic targets for fibrosis and HF.

A global transcriptome analysis of a dog model of congestive heart failure with the human genome as a reference.

BACKGROUND: The global molecular changes in cardiac tissue during congestive heart failure (CHF) have not been fully examined. Transcriptome analysis with the use of next-generation sequencers is a useful tool for elucidating the pathogenesis of CHF. Although there are some advantages in a dog CHF model, transcriptome analyses in dogs are limited by the relative lack of genomic information. METHODS AND RESULTS: The transcriptome analysis of hearts from dogs with CHF was conducted with the use of a genome analyzer and the Casava software. The mRNA sequence reads showed alignments with ∼800 of 1,019 genes from the dog reference database. On the other hand, the reads aligned with ∼15,000 of the 21,407 genes in the hg19 human reference database. The correlation of expressed genes was extremely high (r = 0.93; P < .0001) between the dog and human databases. A pathway analysis using the hg19 reference revealed increased expression of p53 pathway-related (P < 10(-10)) and inflammatory interleukin-related (P < 10(-10)) genes in the CHF model. CONCLUSIONS: The use of the human genome as a reference in global transcriptome analyses of dogs is a useful approach for investigating diseases such as CHF. Such an approach would also be useful for analyzing disease models in other experimental animals.