title: Deletion of FoxO1 leads to shortening of QRS by increasing Na(+) channel activity through enhanced expression of both cardiac NaV1.5 and β3 subunit.
abstract: Our in vitro studies revealed that a transcription factor, Forkhead box protein O1 (FoxO1), negatively regulates the expression of NaV1.5, a main α subunit of the cardiac Na(+) channel, by altering the promoter activity of SCN5a in HL-1 cardiomyocytes. The in vivo role of FoxO1 in the regulation of cardiac NaV1.5 expression remains unknown. The present study aimed to define the role of FoxO1 in the regulation of NaV1.5 expression and cardiac Na(+) channel activity in mouse ventricular cardiomyocytes and assess the cardiac electrophysiological phenotype of mice with cardiac FoxO1 deletion. Tamoxifen-induced and cardiac-specific FoxO1 deletion was confirmed by polymerase chain reaction (PCR). Cardiac FoxO1 deletion failed to result in either cardiac functional changes or hypertrophy as assessed by echocardiography and individual ventricular cell capacitances, respectively. Western blotting showed that FoxO1 was significantly decreased while NaV1.5 protein level was significantly increased in mouse hearts with FoxO1 deletion. Reverse transcription-PCR (RT-PCR) revealed that FoxO1 deletion led to an increase in NaV1.5 and Na(+) channel subunit β3 mRNA, but not β1, 2, and 4, or connexin 43. Whole patch-clamp recordings demonstrated that cardiac Na(+) currents were significantly augmented by FoxO1 deletion without affecting the steady-state activation and inactivation, leading to accelerated depolarization of action potentials in mouse ventricular cardiomyocytes. Electrocardiogram recordings showed that the QRS complex was significantly shortened and the P wave amplitude was significantly increased in conscious and unrestrained mice with cardiac FoxO1 deletion. NaV1.5 expression was decreased in the peri-infarct (border-zone) of mice with myocardial infarction and FoxO1 accumulated in the cardiomyocyte nuclei of chronic ischemic human hearts. Our findings indicate that FoxO1 plays an important role in the regulation of NaV1.5 and β3 subunit expressions as well as Na(+) channel activity in the heart and that FoxO1 is involved in the modulation of NaV1.5 expression in ischemic heart disease.
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Benzhi
authors: B
authors: Cai
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors: Ning
authors: N
authors: Wang
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Weike
authors: W
authors: Mao
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Tao
authors: T
authors: You
authors: Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY, USA; Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors: Yan
authors: Y
authors: Lu
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Xiang
authors: X
authors: Li
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Bo
authors: B
authors: Ye
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors: Faqian
authors: F
authors: Li
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: HaodongXu@mednet.ucla.edu.
authors: Haodong
authors: H
authors: Xu
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D015398:Signal Transduction; D062549:Voltage-Gated Sodium Channel beta-3 Subunit / Q000235:genetics* / Q000378:metabolism
chemical_list: D018031:Connexin 43; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D062549:Voltage-Gated Sodium Channel beta-3 Subunit
keywords: Cardiac depolarization; FoxO1; Na(+) channel; Na(V)1.5; β3 subunit