Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy

Abstract

Although cardiac hypertrophy has been the subject of intensive investigation, regression of hypertrophy has been significantly less studied, precluding large-scale analysis of the relationship between these processes. In the present study, using pharmacological models of cardiac hypertrophy in mice, expression profiling was performed with fragments of more than 4,000 genes to characterize and contrast expression changes during induction and regression of hypertrophy. Administration of angiotensin II and isoproterenol by osmotic minipump produced increases in heart weight (15 and 45%, respectively) that returned to preinduction size after drug withdrawal. From multiple expression analyses of left ventricular RNA isolated at daily time-points during cardiac hypertrophy and regression, we identified sets of genes whose expression was altered at specific stages of this process. While confirming the participation of 25 genes or pathways previously shown to be altered by hypertrophy, a larger set of 30 genes was identified whose expression had not previously been associated with cardiac hypertrophy or regression. Of the 55 genes that showed reproducible changes during the time course of induction and regression, 32 genes were altered only during induction, and 8 were altered only during regression. This study identified both known and novel genes whose expression is affected at different stages of cardiac hypertrophy and regression and demonstrates that cardiac remodeling during regression utilizes a set of genes that are distinct from those used during induction of hypertrophy.T he heart increases its muscle mass in response to increased wall stress resulting from physiologic or pathologic states. The most characteristic cellular feature of this process is the enlargement of existing myocytes caused by the accumulation of sarcomeric proteins and reorganization of myofibrillar structures. Although this response is initially compensatory, it may progress to a pathologic state. As a result, cardiac hypertrophy is a predictor of cardiac morbidity and mortality, independent of hypertension or other risk factors (1, 2).Analysis of gene expression during the induction of cardiac hypertrophy has revealed a specific transcriptional pattern associated with this process. Early mediators of the hypertrophic transcriptional program include the immediate-early genes (e.g., c-fos, c-myc, c-jun, and Egr1), followed by a cascade of mitogen-activated protein kinases (3-7). These changes contribute to substantial alterations in the expression and organization of sarcomeric and structural proteins (3,8).In contrast to the numerous studies examining the response to induction of hypertrophy, surprisingly few studies have examined genes whose expression is specifically altered during recovery from cardiac hypertrophy. The few studies that have examined gene expression changes during regression have largely focused on a small number of reporter genes such as myosin heavy chain (9, 10) and have not sought to identify new genes expressed spec...

Genome‐wide examination of myoblast cell cycle withdrawal during differentiation

“…Expression ratios were calculated using the SCANALYZE software package . Ratios had a mean close to 1 and an SD of 0.4 for each array, which is comparable to the variation seen in other array studies (Iyer et al, 1999;Friddle et al, 2000).…”

“…Microarrays were prepared, hybridized, and scanned as previously described (Friddle et al, 2000). The library used contained approximately 10,000 IMAGE consortium clones from Research Genetics (Lennon et al, 1996).…”

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.…”

“…While the queries of selected ANG II targets supplied important information on several molecular pathways underlying the physiological and pathophysiological actions of ANG II, an all-inclusive view is provided by the genome-wide transcriptional profiling that offers an opportunity to connect separate pieces of the puzzle through the identification of the new players not intuitively obvious from our present understanding of physiology. 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).…”

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute β-adrenergic stimulation

“…It is widely accepted that alteration of sympathetic input results in significant changes in cardiac growth. For example, subhypertensive doses of norepinephrine and sustained activation of ␤-AR from infusion of Iso induce significant cardiac hypertrophy (22,29). Transgenic mice with cardiac-specific overexpression of the human ␤ 1 -AR have gene dose-dependent cardiac hypertrophy and suffer from histopathological damage and myocardial dysfunction (7).…”