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1 The Institute for Genomic Research, Rockville, MD, USA
2 Boston University Medical Center, Boston, MA, USA
3 The Institute for Genomic Research, Rockville, MD, USA; Department of Biochemistry, The George Washington University, Washington, DC, USA; Department of Statistics, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: jlarkin{at}tigr.org.
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 anti-hypertensive treatments are those that antagonize Ang II. We investigated cardiac gene expression in response to acute (24 hour) and chronic (14 day) infusion of Ang II in mice; 24 hour 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 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 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's disease, hypertension, and high cholesterol has been previously documented in studies of brain tissue, this is the first demonstration of induction of Alzheimer's 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.
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