REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice.
Int J Mol Sci
; 25(12)2024 Jun 12.
Article
in En
| MEDLINE
| ID: mdl-38928166
ABSTRACT
Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3ß. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3ß variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3ß at S9 and upregulation of IL-1ß and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3ß-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
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Signal Transduction
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NF-kappa B
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Myocytes, Cardiac
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Diabetes Mellitus, Experimental
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Glycogen Synthase Kinase 3 beta
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Int J Mol Sci
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: