A module of human peripheral blood mononuclear cell transcriptional network containing primitive and differentiation markers is related to specific cardiovascular health variables.
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 co-expressed 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 (R2 = -0.23), vascular stiffness (R2 = -0.24), and central aortic pressure (R2 = -0.19) and positively correlated with body mass index (R2 = 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.
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America; Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Leni
L
Moldovan
Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Mirela
M
Anghelina
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Taylor
T
Kantor
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Desiree
D
Jones
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Enass
E
Ramadan
Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Yang
Y
Xiang
Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Kun
K
Huang
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America; Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Arunark
A
Kolipaka
Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
William
W
Malarkey
Cardiovascular Clinical Research Institute, Emory University, Atlanta, Georgia, United States of America.
Nima
N
Ghasemzadeh
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America; Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Peter J
PJ
Mohler
Cardiovascular Clinical Research Institute, Emory University, Atlanta, Georgia, United States of America.
Arshed
A
Quyyumi
Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America; Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
Nicanor I
NI
Moldovan
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
D015415:Biomarkers