Functional meta-analysis of double connectivity in gene coexpression networks in mammals.

In functional genomics, the high-throughput methods such as microarrays 1) allow analysis of the relationships between genes considering them as elements of a network and 2) lead to biological interpretations thanks to Gene Ontology. But up to now it has not been possible to find relationships between the functions and the connectivity of the genes in coexpression networks. To achieve this aim, we have defined a double connectivity for each gene by the numbers of its significant negative and positive correlations with the other genes within a given biological condition, or group. Here, based on the analysis of 1,260 DNA microarrays, we show that this double connectivity clearly separates two types of genes, those with a predominantly strong negative connectivity, hub- genes, and those with a predominantly strong positive connectivity, hub+ genes. Interestingly, the hub+ genes concerned transcription factors more often than by chance and, similarly, for the hub- genes concerning miRNA predicted targets. Furthermore, a meta-analysis of GO annotations carried out on 67 groups in humans and rats shows that these two types of genes correspond to a functional biological duality. The hub- genes were mainly involved in basic functions common to all eukaryote cells, whereas the hub+ genes were mainly involved in specialized functions related to cell differentiation and communication. The separation and the biological role of these hub- and hub+ genes provide a powerful new tool for a better understanding of the control and regulation of the key genes involved in cellular differentiation and physiopathological conditions.

Transcriptional alterations in the left ventricle of three hypertensive rat models.

Left ventricular hypertrophy (LVH) is commonly associated with hypertension and represents an independent cardiovascular risk factor. The aim of this study was to test the hypothesis that the cardiac overload related to hypertension is associated to a specific gene expression pattern independently of genetic background. Gene expression levels were obtained with microarrays for 15,866 transcripts from RNA of left ventricles from 12-wk-old rats of three hypertensive models [spontaneously hypertensive rat (SHR), Lyon hypertensive rat (LH), and heterozygous TGR(mRen2)27 rat] and their respective controls. More than 60% of the detected transcripts displayed significant changes between the three groups of normotensive rats, showing large interstrain variability. Expression data were analyzed with respect to hypertension, LVH, and chromosomal distribution. Only four genes had significantly modified expression in the three hypertensive models among which a single gene, coding for sialyltransferase 7A, was consistently overexpressed. Correlation analysis between expression data and left ventricular mass index (LVMI) over all rats identified a larger set of genes whose expression was continuously related with LVMI, including known genes associated with cardiac remodeling. Positioning the detected transcripts along the chromosomes pointed out high-density regions mostly located within blood pressure and cardiac mass quantitative trait loci. Although our study could not detect a unique reprogramming of cardiac cells involving specific genes at early stage of LVH, it allowed the identification of some genes associated with LVH regardless of genetic background. This study thus provides a set of potentially important genes contained within restricted chromosomal regions involved in cardiovascular diseases.

Sodium intake and blood pressure in healthy individuals.

OBJECTIVE: To investigate further the relationships between blood pressure and sodium intake, which have been claimed to exist, but have not been clearly established, in epidemiological studies. DESIGN AND PARTICIPANTS: A 2-year follow up study of a cohort of 296 healthy volunteers working in the same company. RESULTS: Consistent with previously reported findings, covariance analysis in the entire population, including multivariate analysis to examine the potential influence of confounding variables, failed to identify a significant relationship between blood pressure and sodium intake or between their respective changes within 2 years. To test the hypothesis of a heterogeneous distribution of salt sensitivity, we calculated the statistical dependence between blood pressure and sodium intake using the coefficient analysis that quantifies the prevalence of a statistical link between two variables. A significant dependence (P < 0.05) between diastolic (DBP) or systolic (SBP) blood pressure and sodium intake was found in 16 and 5% of the participants, respectively. The analysis of the 2-year changes in blood pressure and sodium intake reinforced our findings. Our finding of a relationship between blood pressure and sodium intake in only a few individuals may explain the lack of a global relationship between these two variables investigated by the covariance analysis in our study.(Rho) CONCLUSION: Our results suggest that 5-16% of healthy individuals have a 'salt-dependent blood pressure' and might benefit from a reduction in dietary salt intake.

Blood pressure and heart rate variability changes during cardiac surgery with cardiopulmonary bypass.

This study investigated patients undergoing elective cardiac surgery to evaluate the effects of cardiopulmonary bypass (CPB) on the spontaneous variability of mean arterial pressure (MAP) and heart rate (HR). Forty-one adult patients receiving different cardiovascular system drugs were included in the study. Patients were divided into three groups: no preoperative pharmacological cardiovascular treatment (n = 12), beta-blocker (BB) (n = 13), and angiotensin-converting enzyme inhibition (ACEI) (n = 16). MAP was recorded before anaesthesia until the end of surgery. MAP and HR variability was analysed in very low- (VLF), low- (LF) and high-frequency bands. The LF spectral component of MAP was observed to decrease in patients under ACEI (-92%) or BB (-87%) following induction of anaesthesia. In addition, during CPB, VLF power decreased in BB group (-67%), and LF power decreased in ACEI group (-77%). Concerning HR, VLF spectral power decreased following anaesthesia in BB group (-74%). In addition, after CPB, VLF power reached lower value in ACEI group than in BB group (P < 0.05). LF spectral power of HR showed a large decrease after CPB in ACEI group (-89%). This study showed that MAP variability did not change during CPB in patients with no preoperative pharmacological cardiovascular treatment, suggesting an unaltered vascular control of MAP. Moreover, the change in LF spectral power of MAP in ACEI and BB groups, suggests that both the renin-angiotensin and sympathetic systems participate to the genesis of LF variability of MAP.

Robust coordination of cardiac functions from gene co-expression reveals a versatile combinatorial transcriptional control.

The necessary overall coordination of cardiac cellular functions is little known at the mRNA level. Focusing on energy production and cardiac contraction, we analyzed microarray data from heart tissue obtained in groups of mice and rats in normal conditions and with a left ventricular dysfunction. In each group and for each function, we identified genes positively or negatively correlated with numerous genes of the function, which were called coordinated or inversely coordinated with the function. The genes coordinated with energy production or cardiac contraction showed the coupling of these functions in all groups. Among coordinated or inversely coordinated genes common to the two functions, we proposed a fair number of transcriptional regulators as potential determinants of the energy production and cardiac contraction coupling. Although this coupling was constant across the groups and unveiled a stable gene core, the combinations of transcriptional regulators were very different between the groups, including one half that has never been linked to heart function. These results highlighted the stable coordination of energy production or cardiac contraction at the mRNA level, and the combinatorial and versatile nature of potential transcriptional regulation. In addition, this work unveiled new transcriptional regulators potentially involved in normal or altered cardiac functional coupling.

The microRNA signature in response to insulin reveals its implication in the transcriptional action of insulin in human skeletal muscle and the role of a sterol regulatory element-binding protein-1c/myocyte enhancer factor 2C pathway.

OBJECTIVE: Factors governing microRNA expressions in response to changes of cellular environment are still largely unknown. Our aim was to determine whether insulin, the major hormone controlling whole-body energy homeostasis, is involved in the regulation of microRNA expressions in human skeletal muscle. RESEARCH DESIGN AND METHODS: We carried out comparative microRNA (miRNA) expression profiles in human skeletal muscle biopsies before and after a 3-h euglycemic-hyperinsulinemic clamp, with TaqMan low-density arrays. Then, using DNA microarrays, we determined the response to insulin of the miRNA putative target genes in order to determine their role in the transcriptional action of insulin. We further characterized the mechanism of action of insulin on two representative miRNAs, miR-1 and miR-133a, in human muscle cells. RESULTS: Insulin downregulated the expressions of 39 distinct miRNAs in human skeletal muscle. Their potential target mRNAs coded for proteins that were mainly involved in insulin signaling and ubiquitination-mediated proteolysis. Bioinformatic analysis suggested that combinations of different downregulated miRNAs worked in concert to regulate gene expressions in response to insulin. We further demonstrated that sterol regulatory element-binding protein (SREBP)-1c and myocyte enhancer factor 2C were involved in the effect of insulin on miR-1 and miR-133a expression. Interestingly, we found an impaired regulation of miRNAs by insulin in the skeletal muscle of type 2 diabetic patients, likely as consequences of altered SREBP-1c activation. CONCLUSIONS: This work demonstrates a new role of insulin in the regulation of miRNAs in human skeletal muscle and suggests a possible implication of these new modulators in insulin resistance.