Deletion of the stress response protein REDD1 prevents impaired cardiac function in diabetic mice

The overwhelming impact of heart failure on morbidity and mortality in obesity and type 2 diabetes requires a deeper understanding of the molecular events that mediate cardiac dysfunction. We recently demonstrated using in vivo and in vitro models of diabetes that upregulation of endoplasmic reticulum stress in cardiomyocytes promoted expression of the stress response protein regulated in development and DNA damage 1 (REDD1). REDD1 has been implicated in diabetes-induced functional deficits in both the retina and kidney; however, a role for REDD1 in diabetes-induced cardiac dysfunction has not been investigated. Thus, we explored the hypothesis that REDD1 contributes to the development of diabetes-induced cardiac dysfunction. To induce diabetes, 6-week old male wild-type and REDD1 knock-out (KO) B6;129 mice were fed a high-fat high-sugar diet (42% kcal fat, 34% sucrose by weight) for 16 weeks; 2 weeks after initiation of the diet, mice were administered low-dose streptozotocin (STZ) for five consecutive days. Non-diabetic control mice were fed a standard rodent diet and received vehicle injections. Mice with a fasting blood glucose level >250mg/dL were defined as diabetic. At 10 weeks of age, transthoracic echocardiogram was evaluated every 2 weeks using a GE Logique small animal echocardiography machine. After 12 weeks of diabetes, left ventricular ejection fraction (EF) was reduced in diabetic wild-type mice as compared to non-diabetic wild-type mice (51.0 +/-9.8% versus 39.5 +/- 5.5%, p = 0.015). Meanwhile, EF in diabetic REDD1 KO mice (47.4 +/- 6.6%) was similar to that observed in non-diabetic REDD1 KO mice (49.6 +/- 6.7%). To investigate a potential cause of the preserved EF in diabetic REDD1 KO mice, tissue homogenates from the left ventricle were examined by PCR analysis. REDD1 mRNA expression in diabetic wild-type mice was enhanced as compared to non-diabetic controls in coordination with increased expression of Tgfb1, as well as expression of the pro-fibrotic genes Fn1, Col1a1, and Col3a1. By contrast, there was no increase in pro-fibrotic mRNA expression in cardiac tissue homogenates from diabetic REDD1 KO mice, as compared to non-diabetic REDD1 KO mice. Overall, the data support a role for REDD1 expression in the development of impaired cardiac function and the pro-fibrotic response of the heart to diabetes. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.