title: The effects of overexpression of the Na+/Ca2+ exchanger on calcium regulation in hypertrophied mouse cardiac myocytes.
abstract: In cardiac hypertrophy and failure it has been shown that the amount of Na/Ca exchanger protein can increase. Several studies have investigated this modification in overt heart failure. However, the role of Na/Ca exchanger overexpression during the development of hypertrophy is unknown. To address this question we investigated Ca2+ regulation in an early stage of cardiac hypertrophy before signs of heart failure occurred and evaluated the role of Na/Ca exchanger overexpression. Cardiac hypertrophy was induced by a constant infusion of angiotensin II (Ang, 1 microg/min/kg) via an osmotic pump for 14 days. Thereafter, ventricular myocytes from either wild type (NON) or transgenic mice overexpressing the Na/Ca exchanger (TR) were isolated. Myocytes were loaded with indo-1 AM or fluo-4 AM to monitor cytoplasmic [Ca2+] with all experiments performed at 37 degrees C. In myocytes exposed to Ang there was an increase in cell capacitance of more than 20% indicating cellular hypertrophy. Ca2+ transients were prolonged in hypertrophied NON myocytes but not in TR myocytes. Action potentials had a less negative plateau in TR myocytes. Sarcoplasmic reticulum (SR) Ca2+ content, measured using rapid caffeine application, was greater in TR myocytes but unaffected by hypertrophy. Ca2+ spark frequency was significantly greater in TR. Na/Ca exchanger overexpression prevented the prolongation of the Ca2+ transient observed in hypertrophy and maintained a similar SR Ca2+ leak suggesting a compensatory role in Ca2+ regulation in hypertrophied cardiac myocytes from transgenic mice. We suggest this compensatory effect is mediated by increased SR Ca2+ content and faster Ca2+ removal via the Na/Ca exchanger.
authors.affiliation: Cellular Electrophysiology, Heart Science Centre, Imperial College London, National Heart & Lung Institute, Harefield Hospital, Hill End Road Harefield, Middlesex UB9 6JH, UK. m.stagg@imperial.ac.uk
authors.forename: Mark A
authors.initials: MA
authors.lastname: Stagg
authors.forename: Aalya H
authors.initials: AH
authors.lastname: Malik
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: MacLeod
authors.forename: Cesare M N
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D022062:Electrophysiologic Techniques, Cardiac; D006984:Hypertrophy / Q000378:metabolism*; D007211:Indoles / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; D019831:Sodium-Calcium Exchanger; C048960:indo-1; D002118:Calcium