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FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress
- Publication Year :
- 2016
- Publisher :
- American Physiological Society, 2016.
-
Abstract
- The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/ .
- Subjects :
- 0301 basic medicine
Male
Physiology
Fluorescent Antibody Technique
Endoplasmic Reticulum
Mitochondria, Heart
Ventricular Function, Left
Rats, Sprague-Dawley
Phenylephrine
Calcium-binding protein
Myocytes, Cardiac
Phosphorylation
Sympathomimetics
Membrane Potential, Mitochondrial
Ventricular Remodeling
Forkhead Box Protein O3
Muscle atrophy
Phospholamban
Echocardiography
Signaling and Stress Response
medicine.symptom
Cardiology and Cardiovascular Medicine
Dynamins
medicine.medical_specialty
Programmed cell death
Cell Survival
Blotting, Western
Citrate (si)-Synthase
Biology
In Vitro Techniques
Real-Time Polymerase Chain Reaction
Electron Transport Complex IV
Mitochondrial Proteins
03 medical and health sciences
Microscopy, Electron, Transmission
Stress, Physiological
Physiology (medical)
Internal medicine
medicine
Animals
Ventricular remodeling
Heart Failure
Autophagy
Calcium-Binding Proteins
Membrane Proteins
Stroke Volume
medicine.disease
Rats
Disease Models, Animal
030104 developmental biology
Endocrinology
Apoptosis
Calcium
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7f67248a5b0f62c3557adc5566db1ee3