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Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

LaDisa JF, Bozdag S, Olson J, Ramchandran R, Kersten JR, Eddinger TJ - PLoS ONE (2015)

Bottom Line: We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture.The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID's for HTN and CVD, and individual genes were associated with the CoA MeSH ID.A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States of America; Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States of America.

ABSTRACT
Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture. Here we present the most comprehensive description of differentially expressed genes (DEGs) to date from the pathology of CoA, which were obtained using this model. Aortic samples (n=4/group) from the ascending aorta that experiences elevated blood pressure (BP) from induction of CoA, and restoration of normal BP after its correction, were analyzed by gene expression microarray, and enriched genes were converted to human orthologues. 51 DEGs with >6 fold-change (FC) were used to determine enriched Gene Ontology terms, altered pathways, and association with National Library of Medicine Medical Subject Headers (MeSH) IDs for HTN, cardiovascular disease (CVD) and CoA. The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID's for HTN and CVD, and individual genes were associated with the CoA MeSH ID. A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA.

No MeSH data available.


Related in: MedlinePlus

(Top) Probes with >2 fold-change and a p-value <0.05 for each comparison were binned based on their expression levels using a minimum of 2, 4, 6 and >8 fold changes. Human genes corresponding to expressed probes on the rabbit chip were determined using orthologue analysis in Better Bunny (Craig et al.—BMC Bioinformatics. 2012 May 8;13:84). Probes without an orthologue human gene and redundant differentially expressed genes (DEGs) were omitted. (Bottom) Unique human orthologue DEGs with >6 FC (indicated within the boxes below) were further studied through GO term, function and pathway analysis, and extensive literature review.
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pone.0133356.g003: (Top) Probes with >2 fold-change and a p-value <0.05 for each comparison were binned based on their expression levels using a minimum of 2, 4, 6 and >8 fold changes. Human genes corresponding to expressed probes on the rabbit chip were determined using orthologue analysis in Better Bunny (Craig et al.—BMC Bioinformatics. 2012 May 8;13:84). Probes without an orthologue human gene and redundant differentially expressed genes (DEGs) were omitted. (Bottom) Unique human orthologue DEGs with >6 FC (indicated within the boxes below) were further studied through GO term, function and pathway analysis, and extensive literature review.

Mentions: Differentially expressed probes for each comparison (i.e. CoA vs Control, Corrected vs Control, and CoA vs Corrected) received from Arraystar were binned based on their expression levels using a minimum of 2, 4, 6 and >8 fold changes (Fig 3). A total of 2,272 and 1,174 probes corresponding to genes with >2 FC were found for the CoA vs Control and Corrected vs Control comparisons, respectively. The CoA vs Corrected comparison yielded substantially fewer probes (447) with >2 FC. Human orthologue analysis of probes with >2 FC in Better Bunny revealed 1,211, 689 and 256 unique DEGs in the CoA vs Control, Corrected vs Control, and CoA vs Corrected comparisons, respectively. When scrutinized at a >6 FC level, the number of DEGs reduced to 133, 112 and 11 for the CoA vs Control, Corrected vs Control, and CoA vs Corrected comparisons, respectively (Fig 3).


Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

LaDisa JF, Bozdag S, Olson J, Ramchandran R, Kersten JR, Eddinger TJ - PLoS ONE (2015)

(Top) Probes with >2 fold-change and a p-value <0.05 for each comparison were binned based on their expression levels using a minimum of 2, 4, 6 and >8 fold changes. Human genes corresponding to expressed probes on the rabbit chip were determined using orthologue analysis in Better Bunny (Craig et al.—BMC Bioinformatics. 2012 May 8;13:84). Probes without an orthologue human gene and redundant differentially expressed genes (DEGs) were omitted. (Bottom) Unique human orthologue DEGs with >6 FC (indicated within the boxes below) were further studied through GO term, function and pathway analysis, and extensive literature review.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4514739&req=5

pone.0133356.g003: (Top) Probes with >2 fold-change and a p-value <0.05 for each comparison were binned based on their expression levels using a minimum of 2, 4, 6 and >8 fold changes. Human genes corresponding to expressed probes on the rabbit chip were determined using orthologue analysis in Better Bunny (Craig et al.—BMC Bioinformatics. 2012 May 8;13:84). Probes without an orthologue human gene and redundant differentially expressed genes (DEGs) were omitted. (Bottom) Unique human orthologue DEGs with >6 FC (indicated within the boxes below) were further studied through GO term, function and pathway analysis, and extensive literature review.
Mentions: Differentially expressed probes for each comparison (i.e. CoA vs Control, Corrected vs Control, and CoA vs Corrected) received from Arraystar were binned based on their expression levels using a minimum of 2, 4, 6 and >8 fold changes (Fig 3). A total of 2,272 and 1,174 probes corresponding to genes with >2 FC were found for the CoA vs Control and Corrected vs Control comparisons, respectively. The CoA vs Corrected comparison yielded substantially fewer probes (447) with >2 FC. Human orthologue analysis of probes with >2 FC in Better Bunny revealed 1,211, 689 and 256 unique DEGs in the CoA vs Control, Corrected vs Control, and CoA vs Corrected comparisons, respectively. When scrutinized at a >6 FC level, the number of DEGs reduced to 133, 112 and 11 for the CoA vs Control, Corrected vs Control, and CoA vs Corrected comparisons, respectively (Fig 3).

Bottom Line: We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture.The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID's for HTN and CVD, and individual genes were associated with the CoA MeSH ID.A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States of America; Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States of America.

ABSTRACT
Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture. Here we present the most comprehensive description of differentially expressed genes (DEGs) to date from the pathology of CoA, which were obtained using this model. Aortic samples (n=4/group) from the ascending aorta that experiences elevated blood pressure (BP) from induction of CoA, and restoration of normal BP after its correction, were analyzed by gene expression microarray, and enriched genes were converted to human orthologues. 51 DEGs with >6 fold-change (FC) were used to determine enriched Gene Ontology terms, altered pathways, and association with National Library of Medicine Medical Subject Headers (MeSH) IDs for HTN, cardiovascular disease (CVD) and CoA. The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID's for HTN and CVD, and individual genes were associated with the CoA MeSH ID. A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA.

No MeSH data available.


Related in: MedlinePlus