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P21 activated kinase-1 as a key regulator of cardiac automaticity and excitability

M. Lei,1 X. Wang,1 Y. Ke2 and R.J. Solaro,2 1Institute of Cardiovascular Science, Faculties of Medicine and Human Science and Life Science, University of Manchester, Manchester M13 9NT, UK and 2Department of Physiology and Biophysics, University of Illinois at Chicago, USA.

Cardiac electrical function is highly regulated on a beat to beat basis by multiple extra- and intra-cellular signalling pathways that operate through the modulation of the activity and properties of the ion channels across the membrane of the heart cells. How such regulation is designed to maintain cardiac electrical function under physiological conditions, and how it comes into play in the face of disease conditions are important issues to be addressed. Our recent studies suggest a novel role of P21 activated kinase-1 (Pak1) in regulating cardiac electrical and contractile functions (Ke et al., 2007; Liu et al., 2011).

The present study thereby aims at further clarifying the mechanisms underlying the critical roles of Pak1 in regulating cardiac electrical function and its therapeutic potential in cardiac arrhythmogenesis. We developed a mouse model carrying a cardiomyocyte-restricted deletion of Pak1 (Pak1CKO). Pak1CKO mice displayed relative high basal heart rate with generally normal electrocardiography (ECG) parameters such as P-R, QRS and QT intervals compared with their control littermates Pak1f/f mice. To evaluate ventricular arrhythmic vulnerability, both Pak1CKO and Pak1f/f (control) mice were subjected to acute stress by either treating the mice with isoprenaline (ISO) in vivo (1 mg/kg, i.p), or an ex vivo heart preparation (10-50 nM ISO), or cardiac hypertrophy induced by chronic treatment of ISO (at concentration of 100 mg/ml/g bodyweight for two weeks delivered by mini-osmotic pump) (Charles river labs, UK). Pak1CKO mice showed significantly higher incidence of ventricular arrhythmias than Pak1f/f mice in both acute and chronic stress conditions. Ventricular myocytes isolated from Pak1CKO mice displayed disturbances in their rhythmic Ca2+ oscillations, and occurrence of delayed afterdepolarizations. We investigated sarcoplasmic reticulum (SR) and sarco/endoplasmic reticulum calcium ATPase (SERCA) function. The myocytes were stimulated constantly to reach a steady state prior to 10mM caffeine application to empty the SR, then the SR was refilled by constant stimulation. The SR refill rate in Pak1cko myocytes was significantly prolonged, particularly in chronic ISO treatment. The function of SERCA of Pak1f/f & Pak1cko were calculated and a significant reduction in function of SERCA in Pak1cko myocytes was detected under both basal and chronic ISO conditions. Moreover, we found that the Pak1 activator FTY720, a sphingosine-like analog, was able to attenuate ventricular arrhythmias associated with ISO-induced hypertrophy in wild-type mice but failed to exert such an effect on Pak1cko mice, suggesting that the antiarrhyhmic effect of FTY720 likely acts through Pak1 activation.

Our results thus indicate that Pak1 is a key regulator of cardiac automaticity and excitability. As a novel anti-arrhythmic regulator, Pak1 may be a potential therapeutic target for the treatment of cardiac tachyarrhythmias associated with stress conditions.

Ke Y, Lei M, Collins TP, Rakovic S, Mattick PA, Yamasaki M, Brodie MS, Terrar DA, Solaro RJ. (2007) Regulation of L-type calcium channel activity by p21 activated kinase-1 in guinea-pig sino-trial node pacemaker cells. Circulation Research 100: 1317-27.

Liu W, Zi M, Naumann R, Ulm S, Jin J, Taglieri DM, Prehar S, Gui J, Tsui H, Xiao RP, Neyses L, Solaro RJ, Ke Y, Cartwright EJ, Lei M, Wang X. (2011) Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart. Circulation 124: 2702-15.

Where applicable, the authors confirm that the experiments described here conform with European and UK legislation ethical requirements. The research was supported by BHF, MRC and the Wellcome Trust.