PMID- 27694219 OWN - NLM STAT- MEDLINE DCOM- 20170626 LR - 20230729 IS - 1522-1539 (Electronic) IS - 0363-6135 (Print) IS - 0363-6135 (Linking) VI - 311 IP - 6 DP - 2016 Dec 1 TI - FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress. PG - H1540-H1559 LID - 10.1152/ajpheart.00549.2016 [doi] AB - 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 Ca(2+), 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 Ca(2+) cycling, Ca(2+) homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. CI - Copyright (c) 2016 the American Physiological Society. FAU - Chaanine, Antoine H AU - Chaanine AH AUID- ORCID: 0000-0002-9603-7849 AD - Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. FAU - Kohlbrenner, Erik AU - Kohlbrenner E AD - Division of Cardiovascular Diseases, Mount Sinai School of Medicine, New York, New York. FAU - Gamb, Scott I AU - Gamb SI AD - Microscopy and Cell Analysis Core, Department of Biochemistry and Cell Biology, Mayo Clinic, Rochester, Minnesota; and. FAU - Guenzel, Adam J AU - Guenzel AJ AD - Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. FAU - Klaus, Katherine AU - Klaus K AD - Division of Endocrinology, Mayo Clinic, Rochester, Minnesota. FAU - Fayyaz, Ahmed U AU - Fayyaz AU AD - Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. FAU - Nair, K Sreekumaran AU - Nair KS AD - Division of Endocrinology, Mayo Clinic, Rochester, Minnesota. FAU - Hajjar, Roger J AU - Hajjar RJ AD - Division of Cardiovascular Diseases, Mount Sinai School of Medicine, New York, New York. FAU - Redfield, Margaret M AU - Redfield MM AD - Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; redfield.margaret@mayo.edu. LA - eng GR - P01 HL076611/HL/NHLBI NIH HHS/United States GR - R01 HL105418/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20160930 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (BNIP3 protein, rat) RN - 0 (Calcium-Binding Proteins) RN - 0 (FOXO3 protein, rat) RN - 0 (Forkhead Box Protein O3) RN - 0 (Membrane Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (Sympathomimetics) RN - 0 (phospholamban) RN - 1WS297W6MV (Phenylephrine) RN - EC 1.9.3.1 (Electron Transport Complex IV) RN - EC 2.3.3.1 (Citrate (si)-Synthase) RN - EC 3.6.5.5 (Dnm1l protein, rat) RN - EC 3.6.5.5 (Dynamins) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Blotting, Western MH - Calcium/*metabolism MH - Calcium-Binding Proteins/metabolism MH - Cell Survival MH - Citrate (si)-Synthase/metabolism MH - Disease Models, Animal MH - Dynamins/metabolism MH - Echocardiography MH - Electron Transport Complex IV/metabolism MH - Endoplasmic Reticulum/metabolism MH - Fluorescent Antibody Technique MH - Forkhead Box Protein O3/*genetics/metabolism MH - Heart Failure/*metabolism/physiopathology MH - In Vitro Techniques MH - Male MH - Membrane Potential, Mitochondrial MH - Membrane Proteins/*metabolism MH - Microscopy, Electron, Transmission MH - Mitochondria, Heart/drug effects/*metabolism/ultrastructure MH - Mitochondrial Proteins/*metabolism MH - Myocytes, Cardiac/drug effects/*metabolism/ultrastructure MH - Phenylephrine/pharmacology MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - Real-Time Polymerase Chain Reaction MH - Stress, Physiological MH - Stroke Volume MH - Sympathomimetics/pharmacology MH - Ventricular Function, Left/genetics MH - Ventricular Remodeling PMC - PMC5206339 OTO - NOTNLM OT - BNIP3 OT - FOXO3a OT - apoptosis OT - calcium regulation OT - heart failure EDAT- 2016/10/04 06:00 MHDA- 2017/06/27 06:00 PMCR- 2017/12/01 CRDT- 2016/10/04 06:00 PHST- 2016/08/08 00:00 [received] PHST- 2016/09/13 00:00 [accepted] PHST- 2016/10/04 06:00 [pubmed] PHST- 2017/06/27 06:00 [medline] PHST- 2016/10/04 06:00 [entrez] PHST- 2017/12/01 00:00 [pmc-release] AID - ajpheart.00549.2016 [pii] AID - H-00549-2016 [pii] AID - 10.1152/ajpheart.00549.2016 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2016 Dec 1;311(6):H1540-H1559. doi: 10.1152/ajpheart.00549.2016. Epub 2016 Sep 30.