The Forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy and cell death in post-mitotic cells. Its role in regulating mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BNIP3, modulates mitochondrial morphology and function in HF. We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE) stressed adult cardiac myocytes (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 heart failure with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE stressed ACM with subsequent increases in mitochondrial calcium 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 experimental model of HFpEF decreased BNIP3 expression, reversed adverse LV remodeling and improved LV systolic and particularly, diastolic function with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored PLN phosphorylation at S16 and enhanced DRP1 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 by modulating calcium cycling, calcium homeostasis and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in heart failure, making it an attractive potential therapeutic target.
- Heart Failure
- Calcium Regulation
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology