Reciprocal regulation of myocardial microRNAs and messenger RNA in human cardiomyopathy and reversal of the microRNA signature by biomechanical support - PubMed (original) (raw)

Comparative Study

Reciprocal regulation of myocardial microRNAs and messenger RNA in human cardiomyopathy and reversal of the microRNA signature by biomechanical support

Scot J Matkovich et al. Circulation. 2009.

Abstract

Background: Much has been learned about transcriptional control of cardiac gene expression in clinical and experimental congestive heart failure (CHF), but less is known about dynamic regulation of microRNAs (miRs) in CHF and during CHF treatment. We performed comprehensive microarray profiling of miRs and messenger RNAs (mRNAs) in myocardial specimens from human CHF with (n=10) or without (n=17) biomechanical support from left ventricular assist devices in comparison to nonfailing hearts (n=11).

Methods and results: Twenty-eight miRs were upregulated >2.0-fold (P<0.001) in CHF, with nearly complete normalization of the heart failure miR signature by left ventricular assist device treatment. In contrast, of 444 mRNAs that were altered by >1.3-fold in failing hearts, only 29 mRNAs normalized by as much as 25% in post-left ventricular assist device hearts. Unsupervised hierarchical clustering of upregulated miRs and mRNAs with nearest centroid analysis and leave-1-out cross-validation revealed that combining the miR and mRNA signatures increased the ability of RNA profiling to serve as a clinical biomarker of diagnostic group and functional class.

Conclusions: These results show that miRs are more sensitive than mRNAs to the acute functional status of end-stage heart failure, consistent with important functions for regulated miRs in the myocardial response to stress. Combined miR and mRNA profiling may have superior potential as a diagnostic and prognostic test in end-stage cardiomyopathy.

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Figures

Figure 1. miR expression in human heart failure

(a, Top) Left panel: 28 miRs upregulated by 2.0-fold or greater in failing vs nonfailing hearts, P<0.001 (filled bars) and in post-LVAD vs nonfailing tissue (open bars). Right panel: 4 additional miRs at P<0.01 in failing vs nonfailing hearts. (b, Bottom) Hierarchical clustering of miR expression and sample ID was performed using Euclidean dissimilarity and average linkage (see Supplemental Methods). NF1-11, nonfailing; ICM1-7, ischemic cardiomyopathy; NICM1-10, nonischemic cardiomyopathy; P1-10, post-LVAD. Red indicates low expression, while green indicates high expression. * indicates specimens misclassified by nearest centroid analysis.

Figure 2. mRNA expression in human heart failure

(a, Top) The 50 most upregulated mRNAs in failing hearts (P<0.001); failing vs nonfailing tissue (filled bars), post-LVAD vs nonfailing tissue (open bars). (b, Bottom) Hierarchical clustering of mRNA expression and sample ID was performed using Euclidean dissimilarity and average linkage (see Supplemental Methods). Failing tissue samples are identified by etiology as in Figure 1. Red indicates low expression, while green indicates high expression. * indicates indicates specimens misclassified by nearest centroid analysis.

Figure 3. Hierarchical clustering of miR and mRNA expression profile between nonfailing, heart failure and LVAD-supported subjects

Hierarchical clustering of combined miR and mRNA expression profiles for each subject was performed using Euclidean dissimilarity and average linkage (see Supplemental Methods). Failing tissue samples are identified by etiology as in figure 1 and figure 2. miRs are plotted to the left.

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Reciprocal regulation of myocardial microRNAs and messenger RNA in human cardiomyopathy and reversal of the microRNA signature by biomechanical support - PubMed (original) (raw)