The Role of Redd1 in the Pathophysiology of Diabetes-Induced Cardiac Dysfunction
Open Access
- Author:
- Stevens, Shaunaci
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 28, 2024
- Committee Members:
- Lisa Shantz, Program Head/Chair
Scot Kimball, Major Field Member
Amy Arnold, Outside Unit Member
Christopher Yengo, Outside Field Member
Michael Dennis, Chair & Dissertation Advisor
Elisa Bradley, Special Member - Keywords:
- diabetes
cardiomyopathy
REDD1
ER stress
Inflammation - Abstract:
- Heart failure is a leading cause of mortality and morbidity in patients with diabetes and obesity, yet much remains unknown regarding the molecular events whereby metabolic disease causes myocardial dysfunction. At the cellular level, endoplasmic reticulum (ER) stress and inflammation are considered hallmarks of myocardial impairment. Indeed, the transcription factor NF-κB promotes the expression of a variety of pro-inflammatory cytokines and chemokines and has been previously implicated in the development of cardiac function deficits caused by diabetes. Prior studies from our laboratory demonstrate that the stress response protein regulated in development and DNA damage 1 (REDD1) is upregulated in response to ER stress and contributes to the activation of pro-inflammatory signaling pathways. More specifically, REDD1-dependent activation of the protein kinase glycogen synthase kinase 3β (GSK3β) enhances NF-κB activity in the retina of diabetic mice. However, prior to the studies herein, a role for REDD1 in diabetes-induced myocardial dysfunction had not been previously explored. The studies here investigated the hypothesis that REDD1 plays a maladaptive role in the pathogenesis of heart disease. This hypothesis was explored through three specific aims: (1) investigate regulatory pathways that influence myocardial REDD1 expression in models of diabetes; (2) explore a role for REDD1 in diabetes-induced myocardial inflammation; and (3) define a potential role for REDD1 in cardiac function deficits caused by diabetes. In mice fed a pro-diabetogenic diet, REDD1 mRNA and protein levels in the heart were increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to hyperglycemic/hyperlipidemic culture conditions, REDD1 mRNA expression was increased and pharmacological inhibition of the ER kinase protein kinase RNA-like endoplasmic reticulum kinase (PERK) or knockdown of activating transcription factor 4 (ATF4) prevented an increase in REDD1 mRNA expression. REDD1 deletion reduced pro-inflammatory cytokine levels in the hearts of diabetic mice and in cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions. The expression of a constitutively GSK3β variant (caGSK3β) restored pro-inflammatory cytokine levels in REDD1-deficient cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions. GSK3β knockdown also suppressed NF-κB signaling and other markers of inflammation in cardiomyocytes exposed to hyperglycemic conditions. In cardiomyocytes exposed to hyperglycemic conditions, REDD1 deletion reduced NF-κB activity and caGSK3β expression was sufficient to rescue NF-κB activity in the absence of REDD1. In the hearts of diabetic wild-type mice, left ventricular ejection fraction was reduced as compared to non-diabetic wild-type mice (51.0 +/-9.8% versus 39.5 +/- 5.5%, p = 0.015). Meanwhile, the left ventricular ejection fraction in diabetic REDD1-deficient mice (47.4 +/- 6.6%) was similar to that observed in non-diabetic REDD1-deficient mice (49.6 +/- 6.7%). Overall, the findings of this dissertation support a role for ER stress-induced REDD1 in promoting GSK3β-dependent pro-inflammatory signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.