Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure

Abstract

BackgroundIsoproterenol-induced cardiac hypertrophy in mice has been used in a number of studies to model human cardiac disease. In this study, we compared the transcriptional response of the heart in this model to other animal models of heart failure, as well as to the transcriptional response of human hearts suffering heart failure.ResultsWe performed microarray analyses on RNA from mice with isoproterenol-induced cardiac hypertrophy and mice with exercise-induced physiological hypertrophy and identified 865 and 2,534 genes that were significantly altered in pathological and physiological cardiac hypertrophy models, respectively. We compared our results to 18 different microarray data sets (318 individual arrays) representing various other animal models and four human cardiac diseases and identified a canonical set of 64 genes that are generally altered in failing hearts. We also produced a pairwise similarity matrix to illustrate relatedness of animal models with human heart disease and identified ischemia as the human condition that most resembles isoproterenol treatment.ConclusionThe overall patterns of gene expression are consistent with observed structural and molecular differences between normal and maladaptive cardiac hypertrophy and support a role for the immune system (or immune cell infiltration) in the pathology of stress-induced hypertrophy. Cross-study comparisons such as the results presented here provide targets for further research of cardiac disease that might generally apply to maladaptive cardiac stresses and are also a means of identifying which animal models best recapitulate human disease at the transcriptional level.

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

“…Consistent with our results, the results of microarray analyses available from the NCBI public functional genomics data repository [21,61] showed that the mRNA level of Rnf207 is significantly reduced in NRCs treated with the pyridine activator of myocyte hypertrophy, which induces cardiac hypertrophy [62], and in mouse hearts treated with isoproterenol, which causes tachycardia-induced HF [63].…”

Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice

“…Furthermore, β-blocker treatment, which improves outcomes in HF (35), reduces phosphorylation of RyR2 at Ser2808 and prevents remodeling of the channel complex (34). Consequently, we sought to determine whether the RyR2-S2808A +/+ mice were protected from the detrimental effects of chronic β-adrenergic activation (36,37). Mice were treated with continuous Iso via an osmotic minipump for 8 weeks (30 mg/kg/d) to simulate chronic activation of the SNS.…”

Comparative Phenotypic Assessment of Cardiac Pathology, Physiology, and Gene Expression in C3H/HeJ, C57BL/6J, and B6C3F1/J Mice

“…The increase in circulating catechols in the Prkaa2 knockout mice may be of particular significance because the focal pathology and ECG results observed in the C3H/HeJ mice are consistent with excessive adrenergic tone (Jokinen et al 2005). A mutation in human PRKAG2 that produces a constitutive active form of this protein alters the levels of Prkaa2 activity and leads to a rare form of hypertrophic hCM (Blair et al 2001;Gollob et al 2001). In our study, compared to B6C3F1/J and C57BL/6J mice, C3H/HeJ mice express lowered levels of not only Prkaa2 mRNA, but also of Prkag2 and Prkab2.…”

“…c Genes list below enriched pathways are those that exhibited significant differential expression in the indicated comparison active in the two mouse strains and the F1 hybrid, serves as a driving force behind the electrophysiological remodeling (Galindo et al 2009). Cardiac stress/toxicity causes activation of a fetal gene expression program in cardiac muscle that is considered by some to be an adaptive change.…”