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. 2000 Jun 6;97(12):6745-50.
doi: 10.1073/pnas.100127897.

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

C J Friddle  1 , T Koga, E M Rubin, J Bristow
Affiliations

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

C J Friddle et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
Induction and regression of hypertrophy. Shown is induction and regression of hypertrophy induced by ISO (A) and AII (B). Percent hypertrophy is calculated as the heart/body weight of the drug-treated mice, divided by the heart/body weight of the matched, vehicle-treated controls. Lower curves show body weights on scale to the right. Drug was removed after 7 (A) or 14 (B) days of induction (dashed vertical line). (C) Relative myocyte cross-sectional area was calculated from photomicrographs of AII and ISO treated hearts. Bars represent means of 50 cells +/− SD. *, P < 0.0005.
Figure 2
Figure 2
Expression of atrial natriuretic factor during induction and regression. The log2 of the expression ratio (Drug/Vehicle) as measured by cDNA microarray and quantitative RT-PCR is given for several time points during induction and regression of hypertrophy.
Figure 3
Figure 3
Distribution of gene expression ratios for treated and untreated mice. The distribution of expression ratios for saline- and isoproterenol-treated mice is shown. A shows the mean number of genes, expressed as a percentage of the total number of expressed genes, with a given expression ratio (n = 5). Expression ratios are expressed as the number of standard deviations from the mean. B shows the number of genes that exhibited expression changes greater than 2 SD for zero, one, two, three, four, and five of 5 arrays tested, for vehicle vs. vehicle, ISO vs. vehicle, and AII vs. vehicle.
Figure 4
Figure 4
Confirmation of expression levels by quantitative RT-PCR. The log2 of the expression ratio (Drug/Vehicle) as measured by quantitative RT-PCR is given for several genes at the time points during induction and/or regression that lead to their inclusion in Table 1. P values indicate probability that log2 ratio is different from 0. *, P < 0.05; ‡, P < 0.001.
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