Abstract
Oscillatory breathing (OB) and increased sympathetic nerve activity (SNA) are associated with increased mortality in chronic heart failure (CHF) and may be caused by increased carotid chemoreflex (CC) sensitivity. Reduced blood flow plays an important role in enhanced CC sensitivity. Our objective was to determine if down-regulation of the shear-sensitive transcription factor Krüppel-like Factor 2 (KLF2) mediates increases in CC sensitivity in CHF. Ventilation, renal SNA (RSNA), and ECG was measured at rest and in response to CC activation with isocapnic hypoxia (IsoH). OB was quantified and expressed as the apnea-hypopnea index (AHI). AHI (control 6±1/h, CHF 35±5/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 (all p<0.05 vs. control), as were CC responses to IsoH. Adenoviral transfection of KLF2 to the carotid bodies (CB) in CHF animals resulted in attenuation of AHI (7±2/h), RSNA (18±2 % max), and arrhythmia incidence (46±13/h) (all p<0.05 vs. CHF). CC responses to IsoH were attenuated as well. Protein expression of KLF2 in the CB was decreased in CHF animals, and was restored with adenoviral transfection. Conversely, KLF2 knockdown with lentiviral KLF2 siRNA resulted in decreased CB KLF2 expression and increases in AHI (14±3/h) and RSNA (32±4 % max). Our findings indicate that increased CC sensitivity, OB, and RSNA during CHF may be caused by down-regulation of KLF2 in the CB. This work was supported by NIH PO-1 HL62222, and NIH 1F32HL108592-01A1.
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