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Cardiac-Specific Activation of IKK2 Leads to Defects in Heart Development and Embryonic Lethality.

Kraut B, Maier HJ, Kókai E, Fiedler K, Boettger T, Illing A, Kostin S, Walther P, Braun T, Wirth T - PLoS ONE (2015)

Bottom Line: Expression of IKK2-CA resulted in embryonic lethality around E13.While apoptosis of cardiomyocytes was only increased at later stages, their proliferation was decreased early on, providing an explanation for the disturbed compact zone formation.We conclude that activation of NF-κB is detrimental during normal heart development due to excessive activation of pro-inflammatory pathways.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.

ABSTRACT
The transcription factor NF-κB has been associated with a range of pathological conditions of the heart, mainly based on its function as a master regulator of inflammation and pro-survival factor. Here, we addressed the question what effects activation of NF-κB can have during murine heart development. We expressed a constitutively active (CA) mutant of IKK2, the kinase activating canonical NF-κB signaling, specifically in cardiomyocytes under the control of the α-myosin heavy chain promoter. Expression of IKK2-CA resulted in embryonic lethality around E13. Embryos showed defects in compact zone formation and the contractile apparatus, and overall were characterized by widespread inflammation with infiltration of myeloid cells. Gene expression analysis suggested an interferon type I signature, with increased expression of interferon regulatory factors. While apoptosis of cardiomyocytes was only increased at later stages, their proliferation was decreased early on, providing an explanation for the disturbed compact zone formation. Mechanistically, this could be explained by activation of the JAK/STAT axis and increased expression of the cell cycle inhibitor p21. A rescue experiment with an IκBα superrepressor demonstrated that the phenotype was dependent on NF-κB. We conclude that activation of NF-κB is detrimental during normal heart development due to excessive activation of pro-inflammatory pathways.

No MeSH data available.


Related in: MedlinePlus

Cardiomyocyte-specific expression of IKK2-CA leads to defects in compact zone formation.(A) Hematoxylin/ eosin staining of frontal paraffin sections of control (left) and IKKMyHC embryos (right) at E12.5. RV, right ventricle; LV, left ventricle. Scale bar: 500 μm. Both ventricles of the IKKMyHC embryo show fewer cell layers in the compact zone, and the IKKMyHC heart is generally dilated. (B) Quantification of the number of compact zone cell layers of the right and left ventricles of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05, **P<0.01. (C) Quantification of total heart circumference of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05.
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pone.0141591.g003: Cardiomyocyte-specific expression of IKK2-CA leads to defects in compact zone formation.(A) Hematoxylin/ eosin staining of frontal paraffin sections of control (left) and IKKMyHC embryos (right) at E12.5. RV, right ventricle; LV, left ventricle. Scale bar: 500 μm. Both ventricles of the IKKMyHC embryo show fewer cell layers in the compact zone, and the IKKMyHC heart is generally dilated. (B) Quantification of the number of compact zone cell layers of the right and left ventricles of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05, **P<0.01. (C) Quantification of total heart circumference of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05.

Mentions: Embryonic hearts are characterized by the presence of an inner trabecular and an outer compact zone. Systematic histological examination of the IKKMyHC embryonic hearts at E12.5 showed a significant reduction in the thickness of the compact zone: The compact zones of both ventricles comprised fewer cell layers in comparison to wild type animals (Fig 3A and 3B). Furthermore, measurement of ventricle circumference revealed that the hearts of IKKMyHC animals were slightly enlarged (Fig 3C).


Cardiac-Specific Activation of IKK2 Leads to Defects in Heart Development and Embryonic Lethality.

Kraut B, Maier HJ, Kókai E, Fiedler K, Boettger T, Illing A, Kostin S, Walther P, Braun T, Wirth T - PLoS ONE (2015)

Cardiomyocyte-specific expression of IKK2-CA leads to defects in compact zone formation.(A) Hematoxylin/ eosin staining of frontal paraffin sections of control (left) and IKKMyHC embryos (right) at E12.5. RV, right ventricle; LV, left ventricle. Scale bar: 500 μm. Both ventricles of the IKKMyHC embryo show fewer cell layers in the compact zone, and the IKKMyHC heart is generally dilated. (B) Quantification of the number of compact zone cell layers of the right and left ventricles of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05, **P<0.01. (C) Quantification of total heart circumference of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4634958&req=5

pone.0141591.g003: Cardiomyocyte-specific expression of IKK2-CA leads to defects in compact zone formation.(A) Hematoxylin/ eosin staining of frontal paraffin sections of control (left) and IKKMyHC embryos (right) at E12.5. RV, right ventricle; LV, left ventricle. Scale bar: 500 μm. Both ventricles of the IKKMyHC embryo show fewer cell layers in the compact zone, and the IKKMyHC heart is generally dilated. (B) Quantification of the number of compact zone cell layers of the right and left ventricles of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05, **P<0.01. (C) Quantification of total heart circumference of control and IKKMyHC hearts. N = 6 embryos per group; shown are the arithmetic means +SEM. *P<0.05.
Mentions: Embryonic hearts are characterized by the presence of an inner trabecular and an outer compact zone. Systematic histological examination of the IKKMyHC embryonic hearts at E12.5 showed a significant reduction in the thickness of the compact zone: The compact zones of both ventricles comprised fewer cell layers in comparison to wild type animals (Fig 3A and 3B). Furthermore, measurement of ventricle circumference revealed that the hearts of IKKMyHC animals were slightly enlarged (Fig 3C).

Bottom Line: Expression of IKK2-CA resulted in embryonic lethality around E13.While apoptosis of cardiomyocytes was only increased at later stages, their proliferation was decreased early on, providing an explanation for the disturbed compact zone formation.We conclude that activation of NF-κB is detrimental during normal heart development due to excessive activation of pro-inflammatory pathways.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.

ABSTRACT
The transcription factor NF-κB has been associated with a range of pathological conditions of the heart, mainly based on its function as a master regulator of inflammation and pro-survival factor. Here, we addressed the question what effects activation of NF-κB can have during murine heart development. We expressed a constitutively active (CA) mutant of IKK2, the kinase activating canonical NF-κB signaling, specifically in cardiomyocytes under the control of the α-myosin heavy chain promoter. Expression of IKK2-CA resulted in embryonic lethality around E13. Embryos showed defects in compact zone formation and the contractile apparatus, and overall were characterized by widespread inflammation with infiltration of myeloid cells. Gene expression analysis suggested an interferon type I signature, with increased expression of interferon regulatory factors. While apoptosis of cardiomyocytes was only increased at later stages, their proliferation was decreased early on, providing an explanation for the disturbed compact zone formation. Mechanistically, this could be explained by activation of the JAK/STAT axis and increased expression of the cell cycle inhibitor p21. A rescue experiment with an IκBα superrepressor demonstrated that the phenotype was dependent on NF-κB. We conclude that activation of NF-κB is detrimental during normal heart development due to excessive activation of pro-inflammatory pathways.

No MeSH data available.


Related in: MedlinePlus