Identification of hypertrophy- and heart failure-associated genes by combining in vitro and in vivo models

Abstract

Heart failure (HF) is a complex disease involving multiple changes including cardiomyocyte hypertrophy (growth). Here we performed a set of screens in different HF and hypertrophy models to identify differentially expressed genes associated with HF and/or hypertrophy. Hypertensive Ren2 rats and animals with postmyocardial infarction (post-MI) HF were used as in vivo HF models, and neonatal rat cardiomyocytes treated with hypertrophy inducing hormones phenylephrine, endothelin-1, and isoproterenol were used as in vitro models. This combined approach revealed a robust set of genes that were differentially expressed both in vitro and in vivo. This included known genes like NPPA (ANP) and FHL1, but also novel genes not previously associated with hypertrophy/HF. Among these are PTGIS, AKIP1, and Dhrs7c, which could constitute interesting targets for further investigations. We also identified a number of in vivo specific genes and these appeared to be enriched for fibrosis, wounding, and stress responses. Therefore a number of novel genes within this in vivo specific list could be related to fibroblasts or other noncardiomyocytes present in the heart. We also observed strong differences between the two HF rat models. For example KCNE1 was strongly upregulated in Ren2, but not in post-MI HF rats, suggesting possible etiology-specific differences. Moreover, Gene Ontology analysis revealed that genes involved in fatty acid oxidation were specifically down regulated in the post-MI group only. Together these results show that combining multiple models, both in vivo and in vitro, can provide a robust set of hypertrophy/HF-associated genes. Moreover it provides insight in the differences between the different etiology models and neurohormonal effects.