Cardiac transcriptional response to acute and chronic angiotensin II treatments

Abstract

Exposure of experimental animals to increased angiotensin II (ANG II) induces hypertension associated with cardiac hypertrophy, inflammation, and myocardial necrosis and fibrosis. Some of the most effective antihypertensive treatments are those that antagonize ANG II. We investigated cardiac gene expression in response to acute (24 h) and chronic (14 day) infusion of ANG II in mice; 24-h treatment induces hypertension, and 14-day treatment induces hypertension and extensive cardiac hypertrophy and necrosis. For genes differentially expressed in response to ANG II treatment, we tested for significant regulation of pathways, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Microarray Pathway Profiler (GenMAPP) databases, as well as functional classes based on Gene Ontology (GO) terms. Both acute and chronic ANG II treatments resulted in decreased expression of mitochondrial metabolic genes, notably those for the electron transport chain and Krebs-TCA cycle; chronic ANG II treatment also resulted in decreased expression of genes involved in fatty acid metabolism. In contrast, genes involved in protein translation and ribosomal activity increased expression following both acute and chronic ANG II treatments. Some classes of genes showed differential response between acute and chronic ANG II treatments. Acute treatment increased expression of genes involved in oxidative stress and amino acid metabolism, whereas chronic treatments increased cytoskeletal and extracellular matrix genes, second messenger cascades responsive to ANG II, and amyloidosis genes. Although a functional linkage between Alzheimer disease, hypertension, and high cholesterol has been previously documented in studies of brain tissue, this is the first demonstration of induction of Alzheimer disease pathways by hypertension in heart tissue. This study provides the most comprehensive available survey of gene expression changes in response to acute and chronic ANG II treatment, verifying results from disparate studies, and suggests mechanisms that provide novel insight into the etiology of hypertensive heart disease and possible therapeutic interventions that may help to mitigate its effects.

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

“…dling, and intracellular signaling, observed in experimental models of heart failure induced by pressure overload (32), genetic modifications (8, 32), or drug treatments (12,25,26), suggesting the existence of a common basic mechanism underlying the various aspects of cardiac remodeling in response to different initiating insults.…”

“…Thus simultaneous evaluation of 4,000 genes by the use of microarray technology to query the quantitative changes in left ventricular RNA in response to ANG II-induced progression, and, subsequently, regression of cardiac hypertrophy, revealed a set of genes previously not known to be associated with cardiac hypertrophy (12). Recently, a comprehensive analysis of the cardiac transcriptional response to acute and chronic ANG II treatments has been carried out using microarrays containing 22,000 unique transcript probes (26). One limitation of the microarray technology, however, is its dependence on the genes annotated to date.…”

Impaired myocardial capillarogenesis and increased adaptive capillary growth in FGF2-deficient mice

“…The mechanism(s) leading to the marked capillary growth in response to ANG II-induced myocardial hypertrophy in FGF2-deficient mice remains to be elucidated. It is of note, however, that in a recent study on the cardiac transcriptional response to acute and chronic ANG II treatment in mice Larkin et al 46 found that the response to ANG II infusion in mice is somewhat inconsistent and in general not as marked as in rats. After acute ANG II infusions an increase in blood pressure and related changes in myocardial gene expression, but not in heart weight, was found.…”

“…After acute ANG II infusions an increase in blood pressure and related changes in myocardial gene expression, but not in heart weight, was found. 46 Among the genes differently expressed It seems very unlikely that the physiological role of FGF2 in the adult organism would be inhibition of adaptive capillary growth. Thus, in the absence of FGF2 other growth factors may be upregulated which take over the role normally played by FGF2, thus facilitating capillary growth.…”

From ‘omes to biology

“…A second example of the manner in which we have used data-integration to infer biological meaning is the analysis of a mouse model of hypertension analysed by Jennie Larkin and members of our group in collaboration with Haralambos Gavras of Boston University (Larkin et al 2004). Hypertension is a significant disease affecting one in four Americans and is strongly associated with heart disease, the number one cause of death in the United States.…”