REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice

Activation of the transcription factor NF-kappa B in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-kappa B 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-kappa B signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-kappa B signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNF alpha or hyperglycemic conditions. A similar suppressive effect on NF-kappa B activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3 beta. NF-kappa B activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3 beta variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3 beta at S9 and upregulation of IL-1 beta 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 GSK3 beta-dependent NF-kappa B signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.