RESUMO
OBJECTIVES: Heart failure is typically preceded by myocardial hypertrophy and remodeling, which can be concentric due to pressure overload (PO), or eccentric because of volume overload (VO). The molecular mechanisms that underlie these differing patterns of hypertrophy are distinct and have yet to be fully elucidated. Thus, the goal of this work is to identify novel therapeutic targets for cardiovascular conditions marked by hypertrophy that have previously been resistant to medical treatment, such as a pure VO. METHODS: Concentric or eccentric hypertrophy was induced in rats for 2 weeks with transverse aortic constriction (TAC) or aortocaval fistula (ACF), respectively. Hemodynamic and echocardiographic analysis were used to assess the development of left ventricular (LV) hypertrophy and functional differences between groups. Changes in gene expression were determined by microarray and further characterized with Ingenuity Pathway Analysis. RESULTS: Both models of hypertrophy increased LV mass. Rats with TAC demonstrated concentric LV remodeling while rats with ACF exhibited eccentric LV remodeling. Microarray analysis associated eccentric remodeling with a more extensive alteration of gene expression compared with concentric remodeling. Rats with VO had a marked activation of extracellular matrix genes, promotion of cell cycle genes, downregulation of genes associated with oxidative metabolism, and dysregulation of genes critical to cardiac contractile function. Rats with PO demonstrated similar categorical changes, but with the involvement of fewer individual genes. CONCLUSIONS: Our results indicate that eccentric remodeling is a far more complex process than concentric remodeling. This study highlights the importance of several key biological functions early in the course of VO, including regulation of matrix, metabolism, cell proliferation, and contractile function. Thus, the results of this analysis will inform the ongoing search for new treatments to prevent the progression to heart failure in VO.
RESUMO
Winter wheat lines can achieve cold acclimation (development of tolerance to freezing temperatures) and vernalization (delay in transition from vegetative to reproductive phase) in response to low non-freezing temperatures. To describe cold-acclimation-specific processes and pathways, we utilized cold acclimation transcriptomic data from two lines varying in freeze survival but not vernalization. These lines, designated freeze-resistant (FR) and freeze-susceptible (FS), were the source of crown tissue RNA. Well-annotated differentially expressed genes (p ≤ 0.005 and fold change ≥ 2 in response to 4 weeks cold acclimation) were used for gene ontology and pathway analysis. "Abiotic stimuli" was identified as the most enriched and unique for FR. Unique to FS was "cytoplasmic components." Pathway analysis revealed the "triacylglycerol degradation" pathway as significantly downregulated and common to both FR and FS. The most enriched of FR pathways was "neighbors of DREB2A," with the highest positive median fold change. The "13-LOX and 13-HPL" and the "E2F" pathways were enriched in FR only with a negative median fold change. The "jasmonic acid biosynthesis" pathway and four "photosynthetic-associated" pathways were enriched in both FR and FS but with a more negative median fold change in FR than in FS. A pathway unique to FS was "binding partners of LHCA1," which was enriched only in FS with a significant negative median fold change. We propose that the DREB2A, E2F, jasmonic acid biosynthesis, and photosynthetic pathways are critical for discrimination between cold-acclimated lines varying in freeze survival.
