Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA, USA.
J Physiol. 2018 Aug;596(15):3171-3185. doi: 10.1113/JP273805. Epub 2017 Oct 11.
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.
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 ( 21%), as were CBC responses (Ve, RSNA) to 10% (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.
增强颈动脉体化学感受器反射活动导致呼吸模式紊乱、自主神经调节异常，并增加心力衰竭动物模型心律失常的发生率。颈动脉血流慢性减少与颈动脉体化学感受器活性增加有关。Krüppel 样因子 2（KLF2）是一种剪切力敏感的转录因子，可调节先前已显示在增加化学感受器敏感性中起作用的酶的表达。我们研究了恢复颈动脉体 KLF2 表达对心力衰竭动物模型中化学感受器对通气、交感神经活动、心脏交感神经-迷走神经平衡和心律失常发生率的影响。结果表明，在慢性心力衰竭中恢复颈动脉体 KLF2 可降低交感神经活动和心律失常发生率，并改善心脏交感神经-迷走神经平衡和呼吸稳定性。增加颈动脉体中 KLF2 的治疗方法可能对心力衰竭中的呼吸和自主神经功能障碍有效。
振荡性呼吸和交感神经活动增加（SNA）与心律失常发生率增加有关，并导致慢性心力衰竭（CHF）的死亡率增加。颈动脉体化学感受器反射（CBC）敏感性增加在这一过程中起作用，并且可以由慢性血流减少引发。我们假设，剪切力敏感转录因子 Krüppel 样因子 2（KLF2）的下调介导了 CHF 中 CBC 敏感性的增加，并导致相关的自主神经、呼吸和心脏后果。在假手术和 CHF 兔中，在休息时和 CBC 激活期间测量通气（Ve）、肾交感神经活动（RSNA）和心电图。通过呼吸暂停-低通气指数（AHI）和呼吸率变异性指数（RRVI）来量化振荡性呼吸。CHF 时，AHI（对照 6±1/h，CHF 25±1/h）、RRVI（对照 9±3/h，CHF 29±3/h）、RSNA（对照 22±2%max，CHF 43±5%max）和心律失常发生率（对照 50±10/h，CHF 300±100/h）在休息时增加（均 P<0.05 与对照相比），CBC 对 10%（所有 P<0.05 与对照相比）的反应（Ve、RSNA）也增加。在 CHF 兔中，通过腺病毒转染将 KLF2 转染至颈动脉体，恢复了 KLF2 的表达，降低了 AHI（7±2/h）、RSNA（18±2%max）和心律失常发生率（46±13/h）以及对低氧的 CBC 反应（均 P<0.05 与 CHF 空病毒相比）。相反，颈动脉体中的慢病毒 KLF2 siRNA 降低了 KLF2 的表达，增加了化学感受器的敏感性，并增加了 AHI（6±2/h 与 14±3/h）、RRVI（5±3/h 与 20±3/h）和 RSNA（24±4%max 与 34±5%max）与 scrambled-siRNA 兔相比。总之，颈动脉体中 KLF2 的下调增加了心力衰竭期间颈动脉体化学感受器反射的敏感性、振荡性呼吸、RSNA 和心律失常发生率。
