FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress
FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress
复制标题
DOI：
10.1152/ajpheart.00549.2016
复制
发表时间：
2016-12-01
影响因子：
4.8
通讯作者：
Redfield, Margaret M.
中科院分区：
文献类型：
--
作者：
Chaanine, Antoine H.;Kohlbrenner, Erik;Redfield, Margaret M.
叉头盒O3 a（FOXO 3a）转录因子已被证明可以调节有丝分裂后细胞的葡萄糖代谢、肌肉萎缩和细胞死亡。其在线粒体和心肌功能调节中的作用尚未得到充分研究。基于先前的工作，我们假设FOXO 3a通过BCL 2/腺病毒E1 B 19-kDa蛋白相互作用蛋白3（BNIP 3）调节心力衰竭（HF）中的线粒体形态和功能。我们在体外调节正常和苯肾上腺素（PE）应激的成年心肌细胞（ACM）中的FOXO 3a-BNIP 3途径，并开发了编码显性阴性FOXO 3a（AAV 9. dn-FX 3a）用于在射血分数保留的HF（HFpEF）大鼠模型中进行基因递送。我们发现FOXO 3a上调BNIP 3在正常和PE应激ACM中的表达，随后线粒体Ca 2+增加，导致线粒体膜电位降低，线粒体碎片化和细胞凋亡。而dn-FX 3a减弱了PE应激的ACM中BNIP 3表达的增加及其后果，AAV 9.在HFpEF的实验模型中，dn-FX 3a递送降低了BNIP 3表达，逆转了不利的左心室重构，并改善了左心室收缩功能，特别是舒张功能，同时改善了线粒体结构和功能。此外，AAV 9. dnFX 3a在S16恢复受磷蛋白磷酸化，并在S637增强动力蛋白相关蛋白1磷酸化。此外，FOXO 3a上调参与线粒体凋亡、自噬和心脏萎缩的适应不良基因。我们的结论是，FOXO 3a激活心脏应激是适应不良的，因为它调节Ca 2+循环，Ca 2+稳态，线粒体的动力学和功能。我们的研究结果表明FOXO 3a在HF中的重要作用，使其成为一个有吸引力的潜在治疗靶点。
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. dnFX3a 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.