Genome-wide expression patterns in physiological cardiac hypertrophy
© Drozdov et al; licensee BioMed Central Ltd. 2010
Received: 6 June 2010
Accepted: 11 October 2010
Published: 11 October 2010
Physiological left ventricular hypertrophy (LVH) involves complex cardiac remodeling that occurs as an adaptive response to chronic exercise. A stark clinical contrast exists between physiological LVH and pathological cardiac remodeling in response to diseases such as hypertension, but little is known about the precise molecular mechanisms driving physiological adaptation.
In this study, the first large-scale analysis of publicly available genome-wide expression data of several in vivo murine models of physiological LVH was carried out using network analysis. On evaluating 3 million gene co-expression patterns across 141 relevant microarray experiments, it was found that physiological adaptation is an evolutionarily conserved processes involving preservation of the function of cytochrome c oxidase, induction of autophagy compatible with cell survival, and coordinated regulation of angiogenesis.
This analysis not only identifies known biological pathways involved in physiological LVH, but also offers novel insights into the molecular basis of this phenotype by identifying key networks of co-expressed genes, as well as their topological and functional properties, using relevant high-quality microarray experiments and network inference.
Physiological left ventricular hypertrophy (LVH) is a complex cardiac adaptive response to chronic exercise , sometimes referred to as the "athletic heart" . It is characterized by an increase in left ventricular (LV) mass, wall thickness and chamber size, underpinned by profound molecular and biochemical changes, that allows the heart to efficiently provide an increased cardiac output during periods of exercise . The physiological LVH state can typically be maintained for months or years without significant compromise of cardiac function. In contrast, pathological LVH occurring in response to chronic cardiac overload, imposed by diseases such as hypertension, is characterized by a progression to contractile dysfunction and heart failure and an increased long-term mortality . Other differences between physiological and pathological LVH include the occurrence of significant fibrosis and capillary rarefaction in the latter condition. Due to the stark clinical contrast between physiological and pathological LV remodeling, it is of importance to delineate the precise molecular mechanisms that drive these divergent responses to stress.
Some progress has been made in elucidating mechanisms of physiological hypertrophy through a number of genomic analyses and several reports implicate activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway as an important component . More recent studies offer the possibility to examine gene expression patterns in this phenotype more consistently and broadly [4, 5]. However, restrictions still exist, primarily due to an innate heterogeneity of signaling cascades and limitations of conventional statistical methods to address higher order relationships between genes. Visualization and analysis of biological data as networks is a powerful explorative alternative with the capacity to accurately assess complex relationships and eliminate noise inherent to microarray experiments . Although such methods have already been successful in defining miRNA signature in obesity and diabetes , discovering novel cancer-associated genes , and predicting the involvement of genes in core biological processes , their use in cardiovascular biology has been limited .
Recent availability of comprehensive mouse cardiac hypertrophy microarray datasets, deposited in resources such as ArrayExpress  and Gene Expression Omnibus , makes it possible to investigate global molecular mechanisms of this phenotype. The inference of gene relevance networks by co-expression analysis is based on the hypothesis that genes encoding proteins participating in the same pathway or biological process may often be co-regulated under a large number of experimental conditions . An important advantage of network analysis algorithms is their ability to exploit local structure between biologically related nodes, thus eliminating most of the inherent noise . Additionally, confidence in network inference through co-expression analysis may be increased by an integrative approach that utilizes multiple datasets across a variety of experimental conditions and microarray platforms .
In this study, a computational approach has been undertaken that identifies key expression patterns of physiological LVH using integrative analysis of 3 million gene co-expressions across 141 relevant microarray conditions. We included transcriptome data from studies in mouse models of physiological LVH induced by swimming exercise, cardiac-specific activation of Akt, and cardiac-specific activation of PI3K. This is the first study in cardiac hypertrophy at this scale and it may provide a basis for further understanding of both physiological and pathological LVH phenotypes.
Generation of Microarray co-expression Networks
Gene expression profiles in heart tissue were investigated under normal conditions, during physiological (exercise) stress, and in two gene-modified models of physiological LVH involving cardiac activation of the PI3K/Akt pathway. To estimate the specificity of the hypertrophic gene signature, an additional dataset monitoring gene expression in healthy mouse organs was also used.
Summary of microarray datasets included in the analysis.
No. of Probes
Normalized No. of Probes
Wild Type, Short-term Akt1 induction (n = 12)
Wild Type, caPI3K, dnPI3K
(n = 9)
Wild Type, Short-term exercise, long-term exercise
(n = 30)
Healthy tissue (n = 90)
Network Statistics at PCC = 0.70 for mouse microarray networks and the Conserved network.
Co-expression model of Physiological cardiac hypertrophy
To evaluate the statistical significance of the Conserved network, three randomized networks were generated. Randomization was performed by shuffling edges of the Akt, PI3K, and Swimming networks 4× (number of edges) times, while preserving the node degrees of the original networks  This procedure was repeated 200 times (see Methods). The simulation showed that on average, the three random networks shared 1519 co-expressed genes (standard deviation = 35) and that at most their intersection contained 1641 genes (Figure 2B). These results indicated that identification of 2128 genes in the Conserved network is statistically significant (z-score = 17.1).
Phenotype specificity of the Conserved network was estimated by comparing it to gene co-expressions inferred from the Normal mouse transcriptome (3983 genes, 91544 interactions; PCC≥0.70) . It was hypothesized that the extent of conserved nodes and edges between two networks may correspond to molecular mechanisms shared by the LVH phenotype and cells under basal conditions. Interestingly, it was determined that the Conserved and Normal networks shared only 88 genes and 57 co-expressions, confirming that the Conserved network may reflect LVH-specific cardiac response.
To gauge the extent of validated molecular pathways in all co-expression networks, all genes were mapped to the KEGG pathway database . Genes with annotations in KEGG pathways were considered to be true positives and network precision (specificity) was estimated as the proportion of true positive genes to the overall number of genes in a network (true positive cases plus presumed false positives). At PCC = 0.70, network precision for the Akt, PI3K, Swimming, and Conserved networks approached 31%. Interestingly, it was noted that while increasing PCC threshold had no apparent effect on specificity of individual microarray networks, specificity of the Conserved network increased up to two-fold with PCC values (Figure 2C), suggesting that gene pairs with high PCCs in the Conserved network are likely to be well-annotated molecular entities.
The generation of a Conserved network for physiological cardiac hypertrophy consisting of 2128 genes (Additional file 1) and 4144 interactions (Additional file 2), based on a series of relevant microarray experiments and computational processing of gene expression similarities, is thus a first step towards the discovery of the molecular underpinnings of this phenotype, its basic components and their structural and functional features.
Identification of Critical Hubs in the Conserved co-expression Network
To test the hypothesis that hub genes may be crucial to the overall structure of the discovered network, the 200 most connected genes were systematically removed from the network. To assess network integrity, average betweenness and characteristic path length (see Methods) were measured. Betweenness did not change drastically following systematic removal of the top connected nodes compared to random node removal (Figure 4C). However, systematic removal of hubs increased characteristic path length to a threshold beyond which it rapidly collapsed due to splintering of the core network into small subnetworks. Characteristic path length was unaffected by removal of random genes and the network remained intact (Figure 4D).
It was then of interest to identify biological processes represented by the core network. Of 1020 core genes, 176 participated in 'DNA-dependent regulation of transcription', 171 in 'Transport', and 117 in 'Transcription'. Additionally, the 1020 genes were mapped to KEGG pathways such as 'Oxidative phosphorylation' (n = 19 genes), 'MAPK signaling pathway (n = 18 genes), and 'Focal adhesion' (n = 17 genes) (Figure 4E). Evidently, not all genes can be associated with GO or KEGG classes.
Thus, the generation of a core network for physiological cardiac hypertrophy reduces the initial number of genes to just over a thousand and consequently allows the further study of a more compact dataset, based on topological feature detection. The discovery of both known and newly detected cases in terms of genes and gene sets, along with their functional and evolutionary properties represents a consolidation of information that can be obtained from multiple microarray experiments for this key phenotype.
Physiological stimuli such as chronic exercise lead to compensatory growth and remodeling of the heart associated with preserved or improved cardiac function. Recently, class IA phosphoinositide 3-kinase (PI3K) and Akt1 have emerged as important regulators of physiological adaptation [32, 33] but the broader signaling cascades associated with physiological LVH remain poorly understood. In this study we show that network analysis has the potential to infer genome-wide biological mechanisms related to physiological LVH phenotype. Importantly, we report on the network topology and functional properties of the physiological LVH networks, the first such analysis in a mammalian cardiovascular system.
Gene expression profiles were used to identify conserved gene co-expression patterns in PI3K, Akt1, and Swimming models of physiological LVH and to obtain a global overview of biological functions involved in physiological cardiac remodeling. Previous reports have explored gene co-expression networks derived from heterogeneous microarray platforms [14, 34] and confirm that observing a conserved gene co-expression suggests a biological relevance [9, 35]. The consensus gene co-expression model, referred to as the Conserved network, consisted of 2128 genes and 4144 links (Additional files 1 and 2). It was confirmed to be scale-free, highly structured, and non-random, suggesting the presence of a small number of critical hub genes that may be biologically relevant. Additionally, the Conserved network had only a trivial intersection with the Normal interactome (88 genes, 57 links), suggesting that our consensus model may present a reliable physiological LVH signature. Topological features were consistent with the general behavior of biological networks  and topologies detected in protein-protein interaction collections such as STRING . At PCC≥0.70, 31% of all genes in the Conserved network were identified in the KEGG pathways database. This coverage increased exponentially with PCC threshold, approaching 80% at PCC = 0.88 (Figure 2C). These results are comparable to previous studies of co-expression networks  and suggest that an increase in PCC stringency produces a marked positive effect on network precision.
Due to a large number of co-expression links (3 million), it is possible that some of these links are artifacts or byproducts of systematic error. Thus, evaluation of conserved co-expression links across three physiological LVH networks has a number of strengths compared to conventional statistical approaches. First, reproducible co-expressions are less likely to be false-positives and may reflect biologically relevant links, thus presenting a reliable interactome for further experimental validation [9, 38]. For example, in a recent meta-analysis of >300 tissue samples of gastric cancer, this hypothesis helped to identify a functional link between prognostic marker PLA2G2A and the EphB2 receptor . Second, network intersections account for putative platform- or experiment-dependent variability (e.g. number of transcripts) between multiple microarray datasets . Third, due to the heterogeneous (molecular and physiological) nature of physiological LVH models, conserved co-expressions provide an overview of common regulatory mechanisms.
These assumptions were confirmed using automated PubMed queries, whereby each gene in the Conserved network was searched in the context of 'hypertrophy', 'heart', or 'heart failure'. Indeed, 933 out of 2128 (44%) genes in the Conserved network had at least one abstract per search term while 50 of those have at least one hundred abstracts for all terms, suggesting that the Conserved network provides an acceptable coverage of current molecular knowledge of cardiac biology (Additional file 4).
The Conserved network may be used to describe the regulatory mechanisms underpinning the cardiac remodeling response to physiological stress. 'Oxidative phosphorylation' was noted as one of the most abundant KEGG pathways (n = 27 genes). The most over-represented members of this pathway were genes encoding subunits of mitochondrial cytochrome c oxidase (COX) (n = 6 genes). COX is localized to the inner membrane of mitochondria and is the last component of respiratory chain. To sustain respiration, this enzyme catalyzes the transfer of electrons from cytochrome c to molecular oxygen and facilitates the aerobic production of ATP by ATPsynthase (n = 2 genes in the Conserved network) . To maintain efficient cardiac contractility under increased energetic demand, the regulation of COX function must be preserved. In post-myocardial infarction this mechanism is disrupted by the generation of reactive oxygen species (ROS) such as superoxide, leading to a marked loss of COX activity . These results are consistent with the well-established concept that suppression of mitochondrial energy metabolism can lead to depression of cardiac contractile function .
The Conserved network was useful in the delineation of the cardiac response to increased protein synthesis and energy deprivation through activation of autophagy. This is a highly conserved cellular pro-survival mechanism for bulk lysosomal degradation of cytoplasmic components that mobilizes energy resources in response to starvation or hypoxia . Autophagy also has a protein quality-control housekeeping function. The Conserved network identified two key genes related to autophagic processes, Atg5 (Autophagy-related protein 5) and Becn1 (Beclin-1). Both of these genes were topologically central to the Conserved network (betweenness centrality of 53356.0 and 12262.3 respectively), implicating them in critical mediation of network information flow. Recent studies in mice with temporally controlled cardiac-specific deficiency of Atg5 demonstrated that Atg5 was essential for normal physiological growth and function of the heart. However, Atg5-deficient animals developed contractile dysfunction and heart failure accompanied by increased levels of ubiquitinated proteins. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation . These abnormalities were suggested, at least in part, to be due to loss of the protein quality control function of autophagy. Becn1 is part of a PI3K complex that plays an important role during the initiation of autophagosome formation [42, 44]. Interestingly, mice with heterozygous disruption of Becn1 (Becn1+/-) exhibited reduced levels of autophagy during reperfusion but had decreased apoptosis and reduced infarct size compared to wild type mice , suggesting that in this case autophagy was detrimental. However, Becn1 is an important point of crosstalk with apoptotic pathways through its interaction with anti-apoptotic proteins such as Bcl-2 . Disruption of Becn1 could therefore have pro- or anti-survival effects . Of note, in the Conserved network, Becn1 localized to the same MCL cluster as Bcl-2, which is known to inhibit Becn1-depended autophagy . Thus, in physiological LVH, autophagy compatible with cell survival, rather than cell death, may be regulated by coordinated changes in Atg5, Becn1 and Bcl-2. Indeed, autophagy- and proteolysis-related genes localized to the same cluster as genes involved in cell cycle regulation, providing further support for this hypothesis.
To explore if key regulatory mechanisms may be encoded by topologically significant nodes, the Conserved network was studied using concepts of betweenness centrality and node degree. These approaches are known to detect essential hubs in interaction networks  and previous studies have demonstrated that betweenness is a good indicator of biological essentiality . Interestingly, when the top 200 hub genes were systematically removed from the Conserved network, average network betweenness remained mostly constant and high, while characteristic path length increased dramatically, to a threshold beyond which the network collapsed. This may suggest a presence of a large number of well-connected genes that preserve network information flow, possibly an indicator of maintained functional cardiac integrity during physiological remodeling. Additionally, topologically-central genes (core genes) localized to KEGG pathways including 'Oxidative phosphorylation' (n = 19 genes), 'MAPK signaling pathway' (n = 18 genes), and 'Focal adhesion' (n = 17 genes) (Figure 4E).
Several genes associated with the mammalian target of rapamycin (mTOR) pathway (Cab39, Hif1a, Tsc2) were also identified. The mTOR pathway controls changes in cell size following activation of the PI3K/Akt system. Akt phosphorylates the Tsc2 gene product tuberin, and thereby reduces its ability to stimulate GTP hydrolysis on the Ras-like G protein Rheb, leading to increased protein synthesis via ribosome biogenesis - a key feature of cardiac hypertrophy - and cell growth . Recently, inhibition of the mTOR pathway by rapamycin was demonstrated to alleviate load-induced cardiac hypertrophy in mice, making it a potential therapeutic target . Indeed, Tsc2 had a very large betweenness centrality value (174802.9, top 1%), confirming that it is one of the key constituents of the Conserved network. Core genes present in the 'MAPK signaling pathway' included Map4k3, Map3k7, Rap1a, Mapkapk2, Cacng2, and Ppm1b. Of these, Ppm1b (protein phosphatase 1B) had the greatest node degree (32) and betweenness centrality (73822.0) values, supporting its biological importance. These findings are reinforced by demonstration of direct inhibition of Map3k7 by Ppm1b , thus providing further evidence that Map3k7 activity is reduced in physiological hypertrophy protecting the heart from interstitial fibrosis, severe myocardial dysfunction, and apoptosis .
Similarly, the core Conserved network suggests that the genes involved in KEGG 'Calcium signaling pathway' may be involved in physiological LVH. There were 13 genes (e.g. Ppp3ca, Egfr, Vdac3, Slc25a4, Tnnc1) allocated to 'Calcium signaling pathway', of which Ppp3ca (calcineurin A alpha) had the largest betweenness centrality value (71043.2). Ppp3ca has been shown to be a key regulator of cardiac hypertrophy through activation of the transcription factor NFAT (nuclear factor of activated T-cells) which promotes the expression of pro-hypertrophic genes in concert with other transcription factors such as GATA4 and MEF2 . It can also inhibit Map3k7 signaling . The Conserved network also provides further evidence that calcineurin activity is highly regulated under physiological conditions by elucidation of the Rcn2 gene, which is known to inhibit calcineurin signaling .
The use of MCL in the core network (Figure 5) identified enriched clusters of genes participating in similar biological pathways. For example, cluster 1 was enriched for KEGG pathway 'Apoptosis' (n = 5 genes: Birc2, Irak1, Pik3ca, Prkaca, Ppp3ca). Birc2 (baculoviral IAP repeat-containing 2, betweenness = 3316.0) encodes a protein that inhibits apoptosis by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2. Although previously not reported in the mammalian heart, Birc2 was confirmed as a critical regulator of vascular integrity and endothelial cell survival in zebrafish . Null mutants for Birc2 showed severe hemorrhage and vascular regression due to endothelial cell integrity defects and activation of Caspase-8-dependent apoptosis program. Coordinated regulation of angiogenesis is essential for preserved cardiac contractile function  and our results provide further molecular evidence for angiogenic gene programs in physiological LVH that merits further exploration.
This report presents the first integrative analysis of genome-wide expression data and computational network inference in the context of physiological LVH. The identification of several mechanisms already known to be involved in physiological cardiac remodeling based on prior experimental studies provides confirmation to the validity of the approaches used in this study. In addition to supporting current molecular understanding of the cardiac physiological response to stress, this work characterizes topological and functional properties of 2128 potential molecular targets involved in the systematic regulation of physiological LVH. Additionally, we demonstrate for the first time the evolutionary complexity of the hypertrophic response. Our study suggests that evaluation of higher order relationships between genes and their neighbors, rather than mere individual over- or under-expression, may facilitate a better understanding of function in physiological and pathological phenotypes. Overall, the results offer new support for the utility of co-expression network modeling and the quality of public microarray data in the context of cardiac hypertrophy, facilitating further analysis of complex physiological and pathological phenotypes.
Three publicly available mouse microarray datasets were included in this study, corresponding to 51 arrays. Individual mouse phenotypes under experimental conditions were reviewed carefully to ensure that each met physiological inclusion criteria (LVH with preserved or improved heart function and corresponding normal controls). Raw expression values were obtained from ArrayExpress database  and normalized using Robust Multi-array Average (RMA) . Probesets with very low expression across experiments were removed and, in cases where multiple probesets mapped to a single gene, only those genes with the highest intensities were retained. To standardize annotation across multiple microarray platforms, Affymetrix probe identifiers were mapped to their corresponding Ensembl (August 12, 2009) gene identifiers (IDs) .
Pairwise similarity in gene expression vectors was expressed by the Pearson correlation coefficient (PCC). Gene pairs that correlated above a predefined PCC threshold value were represented in the form of an undirected unweighted network, where nodes (vertices) correspond to genes and links (edges) correspond to co-expression between genes. Randomized networks were generated by rewiring edges in the original networks while preserving the degrees of the respective nodes . The number of rewiring steps taken for each model was 4× (number of edges). This method ensures that topological structure of the network is retained during randomization.
Network consensus and topological analysis
A co-expression link between two genes was considered as a 'consensus' link, if it was observed in all three datasets. Topological properties examined were node degree, network diameter, betweenness centrality, connected components, clustering coefficient, and characteristic path length . Node degree is defined as the total number of edges that connect to a given node. Network diameter is defined as the average shortest path between any pair of nodes in the network. Betweenness centrality is the measure of node importance within a graph, where nodes that occur on many shortest paths between nodes have higher betweenness. Connected components are maximal connected subgraphs of an undirected graph in which any two vertices are connected to each other by edges. Clustering coefficient is the degree to which nodes tend to cluster together. Characteristic path length is the average distance between pairs of vertices.
Cluster Analysis and Functional Enrichment
Significant clusters of genes in a co-expression network were identified using Markov Cluster Algorithm (MCL) . This is an efficient, unsupervised, and accurate graph clustering approach based on simulation of stochastic flow in graphs. To ensure significance of enrichment, only resulting clusters with 10 or more genes were further retained. A distinct advantage of MCL is its ability to avoid incorrect clustering assignments in the presence of false negative edges [6, 62]. This is due to the fact that MCL discovers clusters by virtue of genes sharing higher-order connectivity in their local neighborhoods and not merely pairwise linkages. Genes identified to be present in the same cluster were analyzed for overrepresented (enriched) Gene Ontology Biological Process (GO-BP) terms and KEGG pathways  using the log-odds ratio. Higher ratio indicates a higher relative abundance of a GO-BP term or KEGG pathway in a cluster compared to the entire network. While all KEGG pathways were considered for enrichment, to avoid broad annotation terms, only GO-BP categories with fewer than 1,500 genes (mouse annotations) were retained .
Evolutionary gene analysis
Evolutionary conservation was computed by comparing selected protein sequences from the core network (corresponding to 1020 genes) against the complete genomes of 287 species available in the Complete Genome Tracking (COGENT) database  database using BLAST  with default parameters. Significant hits from this run have been retained with a p-value cut-off < 10-06, corresponding to 100532 pairwise similarity relationships. Homology networks were visualized using the Large Graph Layout (LGL) software .
This work was supported by the British Heart Foundation (BHF) through awards RE/08/003 and CH//99001 (AMS) and a PhD studentship for ID. Parts of this work have been supported by the Network of Excellence ENFIN (contract number LSHG-CT-2005-518254) funded by the European Commission, and the Leducq Fondation.
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