TY - JOUR
T1 - FOXO3A regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress
AU - Chaanine, Antoine H.
AU - Kohlbrenner, Erik
AU - Gamb, Scott I.
AU - Guenzel, Adam J.
AU - Klaus, Katherine
AU - Fayyaz, Ahmed U.
AU - Sreekumaran Nair, K.
AU - Hajjar, Roger J.
AU - Redfield, Margaret M.
N1 - Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/12
Y1 - 2016/12
N2 - The forkhead box 03a (F0X03a) 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 F0X03a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the F0X03a-BNlP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative F0X03a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that F0X03a upregulates BN1P3 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 BN1P3 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, F0X03a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that F0X03a 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 F0X03a in HF, making it an attractive potential therapeutic target. Listen to this article’s corresponding podcast at http://ajpheart. podbean.eom/e/role-of-foxo3a-in-heart-failure/.
AB - The forkhead box 03a (F0X03a) 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 F0X03a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the F0X03a-BNlP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative F0X03a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that F0X03a upregulates BN1P3 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 BN1P3 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, F0X03a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that F0X03a 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 F0X03a in HF, making it an attractive potential therapeutic target. Listen to this article’s corresponding podcast at http://ajpheart. podbean.eom/e/role-of-foxo3a-in-heart-failure/.
KW - Apoptosis
KW - BN1P3
KW - Calcium regulation
KW - F0X03a
KW - Heart failure
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U2 - 10.1152/ajpheart.00549.2016
DO - 10.1152/ajpheart.00549.2016
M3 - Article
C2 - 27694219
AN - SCOPUS:85005959175
SN - 0363-6135
VL - 311
SP - H1540-H1559
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 6
ER -