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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

Gene Ontology (GO) terms for DEGs with >6 FC are shown by biological process (top), molecular function (middle), and cellular component (bottom) domains.Comparison of DEGs was made between groups of samples in three ways: (1) CoA vs Control, (2) Corrected vs Control, and (3) CoA vs Corrected. DEGs common to CoA vs Control and Corrected vs Control are particularly interesting as they could help explain sources of morbidity persisting after restoring BP, as could probes for highly expressed genes in CoA vs Corrected that are not present in the CoA vs Control comparison. These DEGs of potential interesting regions are indicated by black bars, referring back to overlapping DEGs of interest in Fig 4.
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pone.0133356.g005: Gene Ontology (GO) terms for DEGs with >6 FC are shown by biological process (top), molecular function (middle), and cellular component (bottom) domains.Comparison of DEGs was made between groups of samples in three ways: (1) CoA vs Control, (2) Corrected vs Control, and (3) CoA vs Corrected. DEGs common to CoA vs Control and Corrected vs Control are particularly interesting as they could help explain sources of morbidity persisting after restoring BP, as could probes for highly expressed genes in CoA vs Corrected that are not present in the CoA vs Control comparison. These DEGs of potential interesting regions are indicated by black bars, referring back to overlapping DEGs of interest in Fig 4.

Mentions: Venn diagrams of up and down-regulated DEGs with >6 FC common to the CoA vs Control and Corrected vs Control comparisons, as well as DEGs with >6 FC in the CoA vs Corrected comparison that were not found in CoA vs Control comparison, are shown in Fig 4. Details for these DEGs are provided in Table 2 and may be of particular interest in the etiology of morbidity persisting after correction of CoA. GO terms for DEGs with >6 FC within these regions of interest are shown by biological process, molecular function, and cellular component domains in Fig 5.


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)

Gene Ontology (GO) terms for DEGs with >6 FC are shown by biological process (top), molecular function (middle), and cellular component (bottom) domains.Comparison of DEGs was made between groups of samples in three ways: (1) CoA vs Control, (2) Corrected vs Control, and (3) CoA vs Corrected. DEGs common to CoA vs Control and Corrected vs Control are particularly interesting as they could help explain sources of morbidity persisting after restoring BP, as could probes for highly expressed genes in CoA vs Corrected that are not present in the CoA vs Control comparison. These DEGs of potential interesting regions are indicated by black bars, referring back to overlapping DEGs of interest in Fig 4.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133356.g005: Gene Ontology (GO) terms for DEGs with >6 FC are shown by biological process (top), molecular function (middle), and cellular component (bottom) domains.Comparison of DEGs was made between groups of samples in three ways: (1) CoA vs Control, (2) Corrected vs Control, and (3) CoA vs Corrected. DEGs common to CoA vs Control and Corrected vs Control are particularly interesting as they could help explain sources of morbidity persisting after restoring BP, as could probes for highly expressed genes in CoA vs Corrected that are not present in the CoA vs Control comparison. These DEGs of potential interesting regions are indicated by black bars, referring back to overlapping DEGs of interest in Fig 4.
Mentions: Venn diagrams of up and down-regulated DEGs with >6 FC common to the CoA vs Control and Corrected vs Control comparisons, as well as DEGs with >6 FC in the CoA vs Corrected comparison that were not found in CoA vs Control comparison, are shown in Fig 4. Details for these DEGs are provided in Table 2 and may be of particular interest in the etiology of morbidity persisting after correction of CoA. GO terms for DEGs with >6 FC within these regions of interest are shown by biological process, molecular function, and cellular component domains in Fig 5.

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