Cardiac tran-scriptional response to acute and chronic angiotensin II treatments. 10.1152/physiolgenomics.00057.2004.—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 hyper-trophy 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 de-creased 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 treat-ments. 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 metab-olism, whereas chronic treatments increased cytoskeletal and extracellu-lar 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 docu-mented 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. hypertension; renin-angiotensin-aldosterone system; microarray THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) results in the formation of angiotensin II (ANG II) and is a major contributor to hypertension and the resulting target organ damage. ANG II is critical in stimulating physical and meta-bolic changes seen in hypertension, which is why the most effective antihypertensive treatments are those that antagonize the RAAS. Acute increase in ANG II levels elicits an imme-diate rise in blood pressure (BP) due to vasoconstriction and stimulation of other hormones, whereas chronic infusion of ANG II results in damage to vulnerable organs despite the tendency of BP to return toward baseline. Although a 24-h infusion may not produce visible pathological changes, it may alter the expression of genes in various tissues and was shown to produce evidence of myocardial cell damage (62). The earliest pathological changes are seen after 2–3 days of infu-sion and consist of myocyte and renotubular cell necrosis with myocardial and renal scarring (25). Chronic infusions of 1–2 wk duration lead to hypertrophy, necrosis, and fibrosis of the myocardium (71). In the heart, ANG II affects expression of a wide range of genes that underlie these varied physiological responses. ANG II increases the expression of regulatory, structural, and cyto-kine genes that induce cardiac hypertrophy, extracellular ma-trix (ECM) formation, inflammation, and vascular remodeling and regulate BP (11, 64). ANG II also increases reactive oxygen species and oxidative stress and depresses mitochon-drial energy metabolism (55). ANG II upregulates signaling pathways, including mitogen-activated protein kinase (MAPK), RhoA kinase, transforming growth factor-(TGF-), signal transducer and activator of transcription (STATs), and nuclear factor-B (NF-B) pathways. Recent large outcome trials comparing antihypertensive agents have shown that drugs inhibiting the RAAS lead to end-organ protection beyond that attributable to BP lowering (13), thus corroborating the hypothesis that ANG II enhances cardiovascular tissue damage (24). However, little is known about the cellular and molecular alterations that precede and usher the development of visible pathological changes in these tissues. In this study we conducted a comprehensive analysis of gene expression in mice subjected to acute (24 h) and chronic (14 day) exposure to exogenous ANG II. The goal was to evaluate alterations in the expression of genes relevant to cellular integrity, trophic functions, and proliferation that might help us understand the mechanisms triggering the target organ damage seen in RAAS-associated hypertension. To this end, we analyzed regulation of Gene Microarray Pathway Profiler (GenMAPP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and functional classes of genes based on Gene Ontology (GO) term assignments. This infor-mation might be useful in the formulation of rational therapeu-tic interventions addressing specific mechanisms relevant to cardioprotection.