CDK5 promotes ventricular arrhythmogenesis through phosphorylation of N‐type calcium channels in cardiac sympathetic postganglionic neurons

Abstract

Cardiac sympathetic overactivation is an important trigger of fatal ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study found that increased N‐type calcium (Cav2.2) currents in cardiac sympathetic postganglionic (CSP) neurons contributes to cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF rats. Cyclin‐dependent kinase 5 (CDK5), a proline‐directed serine/threonine kinase, has been reported to play an important role in regulation of calcium influx and neurotransmitter release through phosphorylation of Cav2.2α subunit. Our current study aims to investigate whether CDK5 induces cardiac sympathetic overactivation and increases the susceptibility to ventricular arrhythmias via phosphorylation of Cav2.2α in CSP neurons. Lentiviral‐CDK5 cDNA (1×107 TU/ml, 2μl) was in vivo transfected into bilateral stellate ganglia (SG) in sham rats. Nontransfected sham rats served as controls. Final experiments were performed at 9 days after gene transfection. Western blot data demonstrated that gene transfection with lentiviral‐CDK5 cDNA into SGs significantly increased protein expression of CDK5 in CSP neurons in sham rats, compared with nontransfected sham rats. CDK5 cDNA transfection in SGs increased phosphorylation level of Cav 2.2α in CSP neurons from sham rat. The power spectral analysis of heart rate variability in conscious rats demonstrated that overexpression of CDK5 in CSP neurons increased low frequency power and ratio of low frequency to high frequency (index of cardiac sympathetic activation). Additionally, transfection of CDK5 cDNA into CSP neurons markedly increased cardiac sympathetic nerve activity in anesthetized sham rats (45.3±6.4% in sham+CDK5 group vs. 29.2±2.1% in sham group). ECG data obtained from 24‐hour continuous telemetry ECG recording revealed that overexpression of CDK5 in CSP neurons induced heterogeneity of ventricular electrical activities in conscious sham rats, as evidenced by CDK5 cDNA‐elongated ventricular arrhythmia‐related ECG markers including QT interval, QT dispersion, and T‐peak to T‐end interval. More importantly, transfection with CDK5 cDNA into CSP neurons significantly increased the susceptibility to ventricular arrhythmias (arrhythmia score was 1.7±0.9 in sham+CDK5 group vs. 0 in sham group) in anesthetized sham rats. Based on above data, we conclude that CDK5 induces cardiac sympathetic overactivation via phosphorylation of Cav 2.2‐α subunits in CSP neurons, and further increases the susceptibility of ventricular arrhythmias in sham rats.Support or Funding InformationThis study was supported by National Heart, Lung, and Blood Institute Grant (R01HL137832‐01 to Y.‐L. Li)