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KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure

dc.contributor.authorMarcus N.J.
dc.contributor.authorDel Rio R.
dc.contributor.authorDing Y.
dc.contributor.authorSchultz H.D.
dc.date.accessioned2020-09-02T22:22:21Z
dc.date.available2020-09-02T22:22:21Z
dc.date.issued2018
dc.identifier10.1113/JP273805
dc.identifier.citation596, 15, 3171-3185
dc.identifier.issn00223751
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5201
dc.descriptionKey points: Enhanced carotid body chemoreflex activity contributes to development of disordered breathing patterns, autonomic dysregulation and increases in incidence of arrhythmia in animal models of reduced ejection fraction heart failure. Chronic reductions in carotid artery blood flow are associated with increased carotid body chemoreceptor activity. Krüppel-like Factor 2 (KLF2) is a shear stress-sensitive transcription factor that regulates the expression of enzymes which have previously been shown to play a role in increased chemoreflex sensitivity. We investigated the impact of restoring carotid body KLF2 expression on chemoreflex control of ventilation, sympathetic nerve activity, cardiac sympatho-vagal balance and arrhythmia incidence in an animal model of heart failure. The results indicate that restoring carotid body KLF2 in chronic heart failure reduces sympathetic nerve activity and arrhythmia incidence, and improves cardiac sympatho-vagal balance and breathing stability. Therapeutic approaches that increase KLF2 in the carotid bodies may be efficacious in the treatment of respiratory and autonomic dysfunction in heart failure. Abstract: Oscillatory breathing and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid body chemoreflex (CBC) sensitivity plays a role in this process and can be precipitated by chronic blood flow reduction. We hypothesized that downregulation of a shear stress-sensitive transcription factor, Krüppel-like Factor 2 (KLF2), mediates increased CBC sensitivity in CHF and contributes to associated autonomic, respiratory and cardiac sequelae. Ventilation (Ve), renal SNA (RSNA) and ECG were measured at rest and during CBC activation in sham and CHF rabbits. Oscillatory breathing was quantified as the apnoea–hypopnoea index (AHI) and respiratory rate variability index (RRVI). AHI (control 6 ± 1/h, CHF 25 ± 1/h), RRVI (control 9 ± 3/h, CHF 29 ± 3/h), RSNA (control 22 ± 2% max, CHF 43 ± 5% max) and arrhythmia incidence (control 50 ± 10/h, CHF 300 ± 100/h) were increased in CHF at rest (FIO2 21%), as were CBC responses (Ve, RSNA) to 10% FIO2 (all P < 0.05 vs. control). In vivo adenoviral transfection of KLF2 to the carotid bodies in CHF rabbits restored KLF2 expression, and reduced AHI (7 ± 2/h), RSNA (18 ± 2% max) and arrhythmia incidence (46 ± 13/h) as well as CBC responses to hypoxia (all P < 0.05 vs. CHF empty virus). Conversely, lentiviral KLF2 siRNA in the carotid body decreased KLF2 expression, increased chemoreflex sensitivity, and increased AHI (6 ± 2/h vs. 14 ± 3/h), RRVI (5 ± 3/h vs. 20 ± 3/h) and RSNA (24 ± 4% max vs. 34 ± 5% max) relative to scrambled-siRNA rabbits. In conclusion, down-regulation of KLF2 in the carotid body increases CBC sensitivity, oscillatory breathing, RSNA and arrhythmia incidence during CHF. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society
dc.language.isoen
dc.publisherBlackwell Publishing Ltd
dc.subjectapnoea
dc.subjectarrhythmia
dc.subjectcarotid body
dc.subjectheart failure
dc.subjectKrüppel-like Factor 2
dc.subjectoscillatory breathing
dc.subjectsympathetic nerve activity
dc.subjectangiotensin converting enzyme 1
dc.subjectendothelial nitric oxide synthase
dc.subjectkruppel like factor 2
dc.subjectpeptide hydrolase
dc.subjectsmall interfering RNA
dc.subjectunclassified drug
dc.subjectkruppel like factor
dc.subjectadult
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectapnea hypopnea index
dc.subjectArticle
dc.subjectautonomic dysfunction
dc.subjectbreathing disorder
dc.subjectcardiovascular parameters
dc.subjectcarotid body
dc.subjectchemoreceptor reflex
dc.subjectcontrolled study
dc.subjectdown regulation
dc.subjectfractional shortening
dc.subjectheart arrhythmia
dc.subjectheart ejection fraction
dc.subjectheart failure
dc.subjectheart rate variability
dc.subjecthypoxia
dc.subjectin vivo study
dc.subjectleft ventricular diastolic volume
dc.subjectleft ventricular systolic volume
dc.subjectlung minute volume
dc.subjectmale
dc.subjectnerve conduction
dc.subjectNew Zealand White (rabbit)
dc.subjectnonhuman
dc.subjectoscillatory breathing
dc.subjectpriority journal
dc.subjectprotein expression
dc.subjectrenal sympathetic nerve activity
dc.subjectrespiratory rate variability index
dc.subjectrespiratory tract parameters
dc.subjectviral gene delivery system
dc.subjectanimal
dc.subjectapnea
dc.subjectautonomic nervous system
dc.subjectbreathing
dc.subjectcarotid body
dc.subjectchronic disease
dc.subjectheart failure
dc.subjectinnervation
dc.subjectkidney
dc.subjectLeporidae
dc.subjectpathophysiology
dc.subjectphysiology
dc.subjectAnimals
dc.subjectApnea
dc.subjectArrhythmias, Cardiac
dc.subjectAutonomic Nervous System
dc.subjectCarotid Body
dc.subjectChronic Disease
dc.subjectHeart Failure
dc.subjectKidney
dc.subjectKruppel-Like Transcription Factors
dc.subjectMale
dc.subjectRabbits
dc.subjectRespiration
dc.titleKLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure
dc.typeArticle


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