A Module of Human Peripheral Blood Mononuclear Cell Transcriptional Network Containing Primitive and Differentiation Markers Is Related to Specific Cardiovascular Health Variables

• Type of Material: Article
• Authors: Leni Moldovan, Ohio State University; Mirela Anghelina, Ohio State University; Taylor Kantor, Ohio State University; Desiree Jones, Ohio State University; Eness Ramadan, Ohio State University; Yang Xiang, Ohio State University; Kun Huang, Ohio State University; Arunark Kolipaka, Ohio State University; William Malarkey, Ohio State University; Nima Ghasemzadeh, Emory University; Peter J. Mohler, Ohio State University; Arshed Quyyumi, Emory University; Nicanor I. Moldovan, Ohio State University; Young-sup Yoon, Emory University
• Language: English
• Date: 2014-04-23
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: 2014 Moldovan et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0095124
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 4
• Start Page: e95124
• End Page: e95124
• Grant/Funding Information: This study was supported by National Institutes of Health grants RC2 AG-036559 and R01 HL-65983 (http://www.nih.gov).
• Keywords: Multidisciplinary Sciences; STEM-CELLS; MULTIDISCIPLINARY SCIENCES; AORTIC STIFFNESS; Science & Technology; ENDOTHELIAL PROGENITOR CELLS; GENE-EXPRESSION; DISEASE; T-CELLS; Science & Technology - Other Topics; AUGMENTATION INDEX; VASCULAR FUNCTION; BONE-MARROW; MESSENGER-RNA
• Research Categories: Health Sciences, General

Abstract

Peripheral blood mononuclear cells (PBMCs), including rare circulating stem and progenitor cells (CSPCs), have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their coexpressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell-associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene), defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p < 0.03) with age (R 2 = 20.23), vascular stiffness (R 2 = -0.24), and central aortic pressure (R 2 = -0.19) and positively correlated with body mass index (R 2 = 0.72, in women). The co-expression of three neovascular markers was validated at the single-cell level using mRNA in situ hybridization and immunocytochemistry. The overall gene expression in this cardiovascular module was reduced by 72±22% in the patients compared with controls. However, the compactness of both modules was increased in the patients' samples, which was reflected in reduced dispersion of their nodes' degrees of connectivity, suggesting a more primitive character of the patients' CSPCs. In conclusion, our results show that the relationship between CSPCs and vascular function is encoded in modules of the PBMCs transcriptional network. Furthermore, the coordinated gene expression in these modules can be linked to cardiovascular risk factors and subclinical cardiovascular disease; thus, this measure may be useful for their diagnosis and prognosis. © 2014 Moldovan et al.