Abstract
Abstract P2077: FoxO3 Transcription Factor Regulates Myocyte Contractility And Calcium Homeostasis In Diabetic Cardiomyopathy
Circulation research, Vol.133(Suppl_1)
08/04/2023
DOI: 10.1161/res.133.suppl_1.P2077
Abstract
Abstract only Diabetes is a risk factor for heart failure with preserved ejection fractions (HFpEF). Calcium (Ca 2+ ) mishandling and diastolic abnormalities are the characteristics of diabetic cardiomyopathy (DCM), but the molecular mechanisms of these are elusive. FoxO transcription factors (FoxOs) are suppressed by insulin and this study evaluated the role of FoxO3 in myocardial contractility and Ca 2+ handling in the heart of a mouse model of type 1 diabetes. We show that cardiomyocyte-restricted deletion of FoxO3 (H-FoxO3 KO) prevented reduction in the peak rate of left ventricular (LV) pressure (dP/dt max) and prevented the increase in the minimum rate of fall in LV pressure (dP/dt min) that was evident after 4-7 weeks of Streptozotocin (STZ) diabetes. Time for pressure decay of LV while relaxation (Tau) was partially increased in STZ hearts and tended to decrease in STZ H-FoxO3 KO. Echocardiography showed LVEF was unchanged in control and H-FoxO3 KO animals treated with/without STZ. Ca 2+ imaging in perfused hearts found that Ca 2+ transient amplitude was decreased and decay kinetics prolonged (indicates decreased SERCA activity) in STZ hearts, but these changes were prevented in STZ H-FoxO3 KO. Phosphorylation of SERCA at Thr484 by SPEG (Striated muscle preferentially expressed protein kinase) controls Ca 2+ re-uptake and cardiac contractility. We show that STZ diabetes decreases SPEG protein and pSERCA2a Thr484 , but levels of each were normalized or increased in STZ H-FoxO3 KO. Mechanistically, overexpression of FoxO3 in neonatal cardiomyocytes increases high-molecular weight SPEG adducts when proteasome degradation was inhibited with MG-132, suggesting that ubiquitin-mediated degradation of SPEG is a mechanism by which FoxO3 controls Ca 2+ handling via SERCA phosphorylation. SERCA function requires ATP, thus, we evaluated mitochondrial energetics in these animals. Respiratory capacity in saponin-permeabilized cardiac fibers was unchanged in hearts from controls and H-FoxO3 KO treated with/without STZ. ATP generation was decreased in STZ hearts but was not normalized in STZ-H FoxO3 KO. These data indicate FoxO3 regulates myocyte contractility via SPEG degradation to control intracellular Ca 2+ via pSERCA2a Thr484 in the heart in a type 1 diabetes model.
Details
- Title: Subtitle
- Abstract P2077: FoxO3 Transcription Factor Regulates Myocyte Contractility And Calcium Homeostasis In Diabetic Cardiomyopathy
- Creators
- Gourav Bhardwaj - University of IowaChristie Penniman - University of IowaSatya Murthy Tadinada - University of IowaQian Shi - University of IowaBiyi Chen - University of IowaColette Nowers - University of IowaEric T Weatherford - University of IowaEvan dale Abel - University of California, Los AngelesLong-Sheng Song - University of IowaBrian O'Neill - Iowa City, IA
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.133(Suppl_1)
- DOI
- 10.1161/res.133.suppl_1.P2077
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/04/2023
- Academic Unit
- Internal Medicine; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Fraternal Order of Eagles Diabetes Research Center; Cardiovascular Medicine
- Record Identifier
- 9984480345702771
Metrics
5 Record Views