Abstract 12973: Genetic Suppression of Calcium-Dependent Tyrosine Kinase Pyk2 Increases Vulnerability to Ventricular Tachyarrhythmia
Introduction: Proline-rich tyrosine kinase 2 (Pyk2) is a non-receptor protein kinase regulated by intracellular Ca2+, CaMK, and PKC, and can be activated by different stress signals involved in ventricular hypertrophy and heart failure. However, Pyk2 has not been investigated in the human heart, and cardiac in vivo function of Pyk2 signaling has not been elucidated.
Hypothesis: We aimed to estimate an expression of Pyk2 in the human heart, and investigate a functional role of Pyk2 in the mechanism of stress-associated ventricular arrhythmogenesis using a mouse model.
Methods: We detected expression of Pyk2 in non-failing versus ischemic and non-ischemic failing human hearts (n=6/group) by Western blot. To investigate Pyk2 function in vivo , we optically mapped Langendorff-perfused hearts from wild type (WT, n=7) and Pyk2 knockout (Pyk2−/−, n=8) mice in control and during autonomic stimulation. mRNA expression patterns in WT and Pyk2−/− mouse ventricles were examined by transcriptional profiling using Illumina beadarray.
Results: Western blot revealed a two-fold higher level of Pyk2 activation in non-ischemic failing human hearts compared to non-failing hearts. In mouse hearts, we observed a much higher probability of ventricular tachyarrhythmia during ACh perfusion in Pyk2−/− vs WT mice. Parasympathetic stimulation resulted in a dose-dependent decrease of atrial action potential duration (APD) in both WT and Pyk2−/− mice, while in ventricles it induced APD shortening in Pyk2−/− but not WT mice. Lower RNA expression of SERCA2 and higher expression of Cav1.4 were detected in Pyk2−/− mice vs WT. The data are shown in the table.
Conclusions: Our results suggest a protective role of Pyk2 with respect to ventricular tachyarrhythmia during parasympathetic stimulation by regulation of gene expression related to calcium handling. We hypothesize that activation of Pyk2 in the human heart during heart failure may represent a compensatory protection against arrhythmia.
- © 2010 by American Heart Association, Inc.