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Scn3b Knockout Mice Exhibit Abnormal Sino-Atrial and Cardiac Conduction Properties

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Scn3b Knockout Mice Exhibit Abnormal Sino-Atrial and Cardiac Conduction Properties Acta Physiol 2010, 198, 47–59 Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties P. Hakim,1 N. Brice,2 R. Thresher,2 J. Lawrence,2 Y. Zhang,1 A. P. Jackson,3 A. A. Grace1,3 and C. L.-H. Huang1,3 1 Physiological Laboratory, University of Cambridge, Cambridge, UK 2 Takeda Cambridge Limited, Cambridge Science Park, Cambridge, UK 3 Department of Biochemistry, University of Cambridge, Cambridge, UK Received 28 May 2009, Abstract revision requested 16 July 2009, Aim: In contrast to extensive reports on the roles of Nav1.5 a-subunits, there revision received 9 August 2009, have been few studies associating the b-subunits with cardiac arrhythmo- accepted 22 September 2009 Correspondence: C. L.-H. Huang, genesis. We investigated the sino-atrial and conduction properties in the )/) Physiological Laboratory, hearts of Scn3b mice. University of Cambridge, Downing Methods: The following properties were compared in the hearts of wild- ) ) Street, Cambridge CB2 3EG, UK. type (WT) and Scn3b / mice: (1) mRNA expression levels of Scn3b, Scn1b E-mail: [email protected] and Scn5a in atrial tissue. (2) Expression of the b3 protein in isolated cardiac myocytes. (3) Electrocardiographic recordings in intact anaesthe- Re-use of this article is permitted in accordance with the Terms and tized preparations. (4) Bipolar electrogram recordings from the atria of Conditions set out at http:// spontaneously beating and electrically stimulated Langendorff-perfused www3.interscience.wiley.com/ hearts. ) ) authorresources/onlineopen.html Results: Scn3b mRNA was expressed in the atria of WT but not Scn3b / hearts. This was in contrast to similar expression levels of Scn1b and Scn5a mRNA. Immunofluorescence experiments confirmed that the b3 protein was ) ) expressed in WT and absent in Scn3b / cardiac myocytes. Lead I electro- ) ) cardiograms from Scn3b / mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts. Spontaneously beat- ) ) ing Langendorff-perfused Scn3b / hearts demonstrated both abnormal atrial electrophysiological properties and evidence of partial or complete dissociation of atrial and ventricular activity. Atrial burst pacing protocols ) ) induced atrial tachycardia and fibrillation in all Scn3b / but hardly any WT ) ) hearts. Scn3b / hearts also demonstrated significantly longer sinus node recovery times than WT hearts. Conclusion: These findings demonstrate, for the first time, that a deficiency in Scn3b results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular elec- trophysiology reported on an earlier occasion. Keywords atrial arrhythmias, beta3, cardiac electrophysiology, Scn3b, sodium channel. Previous studies have established that genetic modifica- (Roberts & Brugada 2000) and long QT syndromes tions involving the cardiac a-subunit, SCN5A, can result (LQTS) (Wang et al. 1995), but also atrial conditions, in arrhythmic cardiac conditions. These include not such as atrial fibrillation (AF) (Morita et al. 2002, only ventricular conditions such as the Brugada (BrS) Olson et al. 2005, Chen et al. 2007). However, there Ó 2009 The Authors Journal compilation Ó 2009 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2009.02048.x 47 ) ) Sino-atrial function and cardiac conduction in Scn3b / hearts Æ P Hakim et al. Acta Physiol 2010, 198, 47–59 are only a limited number of reports that have consid- and sinus node recovery time (SNRT) protocols ered the possible associations of b-subunits with such respectively. human arrhythmic conditions. The mRNA encoding for these b-subunits are all expressed in human, skeletal and Materials and methods cardiac tissue (Makita et al. 1994, Isom et al. 1995b, Morgan et al. 2000, Stevens et al. 2001, Yu et al. 2003, Experimental animals Candenas et al. 2006). They have a number of possible functions. Firstly, they may regulate the membrane The genetically modified mice used were first described expression density of the Na+ channels themselves (Isom by Hakim et al. (2008). The 129sv mice were kept in et al. 1995b, Chen et al. 2002). Secondly, the b-sub- cages at a room temperature of 21 Æ 1 °C in an animal units contain extracellular immunoglobulin (Ig) loop facility with 12 h light/dark cycles. The mice had free domains that may have functions similar to those of cell access to sterilized rodent chow and water. All male and ) ) adhesion molecules (CAMs) (Isom & Catterall 1996). female offspring of the wild-type (WT) and Scn3b / Finally, these subunits may also modulate gating prop- mice (age 5–8 months) were randomly selected in all erties of the Na+ channel (Isom et al. 1992, 1995a, experiments and were killed by cervical dislocation in Morgan et al. 2000, Chen et al. 2002, Ko et al. 2005, all real-time polymerase chain reaction and ex vivo Hakim et al. 2008). experiments [Schedule 1: UK Animals (Scientific Proce- Recent clinical studies have associated mutations in dures) Act 1986]. the genes encoding for b-subunits with cardiac arrhythmogenesis. One mutation involving the gene Analysis of Na+ channel a- and b-subunit transcripts encoding for the b4 subunit (SCN4B) has been associated with LQT3 (Medeiros-Domingo et al. Analysis of mRNA expression levels of sodium channel 2007). Three mutations involving the gene encoding a- and b-subunits was performed as described in a for the b1 subunit (SCN1B) and one mutation in the previous paper (Hakim et al. 2008), except that mRNA gene encoding for the b3 subunit (SCN3B) have been was isolated from atrial appendages (n = 3). associated with BrS (Watanabe et al. 2008, Hu et al. 2009). Similarly, there have been relatively few studies Cardiac myocyte isolation and immunolocalization of in murine models containing b-subunit mutations Scn3b subunits examining cardiac arrhythmogenesis. Electrocardio- grams (ECGs) from mice lacking the Scn1b gene A basic isolation buffer consisting of (in mm): 120 showed longer RR intervals and prolonged QT NaCl, 5.4 KCl, 5 MgSO4, 5.5 sodium pyruvate, 10 intervals compared to those shown in WT hearts glucose, 20 taurine and 10 HEPES was used to make the (Lopez-Santiago et al. 2007). Additionally, ventricular following solutions. Firstly, a nitrilotriacetic acid (NTA) tachycardia induced by programmed electrical stimula- buffer consisted of the basic isolation buffer with 5 mm tion was demonstrated in Langendorff-perfused hearts NTA and adjusted to pH 6.95. Secondly, a digestion ) ) isolated from Scn3b / mice (Hakim et al. 2008). buffer consisted of the basic isolation buffer to which )1 The present study adds to the latter investigation, 0.25 mm CaCl2, 1 mg mL collagenase type 2 (Wor- ) which was confined to examining ventricular electro- thington, Lakewood, NJ, USA) and 1 mg mL 1 hyal- physiology. It goes on to associate the deletion of the uronidase (Sigma-Aldrich, Poole, UK) was added. Scn3b gene with abnormal atrial electrophysiology, as Thirdly, a stop buffer consisted of the basic isolation ) well as atrial-ventricular (A-V) block, conduction buffer and containing 2 mg mL 1 bovine serum albu- abnormalities and atrial arrhythmias. The following min (Sigma-Aldrich). Fourthly, a wash buffer consisted properties were compared in the hearts of WT and of the basic isolation buffer to which 0.6 mm CaCl2 was ) ) Scn3b / mice. Firstly, mRNA expression levels of added. Finally, a storage buffer was similar to the wash Scn3b, Scn1b and Scn5a were explored in atrial tissue. buffer but contained 1.2 mm CaCl2. All the buffers Secondly, expression of b3 proteins was investigated in created, except for the NTA buffer, had their pH isolated cardiac myocytes using immunofluorescence adjusted to 7.4. methods. Thirdly, ECGs were investigated in intact Hearts from adult mice were rapidly excised and anaesthetized mice. Finally, electrophysiological prop- submerged in ice-cold isolation buffer. The hearts erties of isolated Langendorff-perfused hearts were were then retrogradely perfused for 2 min with NTA assessed using bipolar electrogram (BEG) recordings. buffer using a variable speed peristaltic pump at a ) The latter were obtained from the atrial appendages of flow rate of 3.5 mL min 1 (model EV045; Autoclude spontaneously beating and electrically stimulated Peristaltic Pumps, Essex, UK). Before perfusion, the hearts. Arrhythmogenicity and sinus node function buffer was warmed to 37 °C with a water jacket and was also investigated using atrial burst pacing (ABP) circulator (Techne model RB-5 A; Bibby Scientific Ó 2009 The Authors 48 Journal compilation Ó 2009 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2009.02048.x ) ) Acta Physiol 2010, 198, 47–59 P Hakim et al. Æ Sino-atrial function and cardiac conduction in Scn3b / hearts Limited, Staffordshire, UK). Immediately following ) ) Surface ECG recordings in WT and Scn3b / mice this, the NTA buffer was replaced with the digestion buffer and perfused in the same fashion for 12– ECG recordings were recorded from randomly selected 15 min. Using watchmaker’s forceps, tissue was taken male and female mice (age 6 months). Prior to exam- from the whole heart and placed in the stop buffer. ination, each mouse was anaesthetized using an intra- After transferring into a 15 mL test tube, single peritoneal injection of ketamine/xylazine (150 and myocytes were isolated from the harvested cardiac 5 mg/kg respectively). Fifteen minutes after administra- tissue through gentle trituration. After allowing 5 min tion of the anaesthetic, the mice were placed on a for the cells to settle, the supernatant was then gently custom-made heat block to maintain body temperature removed and the cells were washed using the wash during data acquisition. Lead I ECGs were obtained buffer. Following a further 5 min, the isolated myo- using subcutaneous 29-gauge needle electrodes (ADIn- cytes were resuspended and stored in the storage struments, Oxfordshire, UK), inserted in the left and buffer. After each step following the harvesting of the right foreleg. These signals were pre-amplified using an cells, isolated myocytes were checked under a light NL100AK headstage and amplified with an NL104A microscope.
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