Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K+ Currents With Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K+ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QTc intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (Cm) was higher, and Ito,f, IK,slow, Iss, and IK1 densities were lower in TAC, than in sham, LV myocytes. Although the primary determinant of the reduced current densities is the increase in Cm, IK,slow amplitudes were decreased and Iss amplitudes were increased in TAC LV cells. Further experiments revealed regional differences in the effects of LVH. Cellular hypertrophy and increased Iss amplitudes were more pronounced in TAC endocardial LV cells, whereas IK,slow amplitudes were selectively reduced in TAC epicardial LV cells. Consistent with the similarities in Ito,f and IK1 amplitudes, Kv4.2, Kv4.3, and KChIP2 (Ito,f), as well as Kir2.1 and Kir2.2 (IK1), transcript and protein expression levels were similar in TAC and sham LV. Unexpectedly, expression of IK,slow channel subunits Kv1.5 and Kv2.1 was increased in TAC LV. Biochemical experiments also demonstrated that, although total protein was unaltered, cell surface expression of TASK1 was increased in TAC LV. Functional changes in repolarizing K+ currents with LVH, therefore, result from distinct cellular (cardiomyocyte enlargement) and molecular (alterations in the numbers of functional channels) mechanisms.

[1]  F. Sachse,et al.  The acid-sensitive potassium channel TASK-1 in rat cardiac muscle. , 2007, Cardiovascular research.

[2]  J. Nerbonne,et al.  Molecular physiology of cardiac repolarization. , 2005, Physiological reviews.

[3]  Attila Kovacs,et al.  The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. , 2003, The Journal of clinical investigation.

[4]  H. Duff,et al.  Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels. , 2003, Cardiovascular research.

[5]  J. Nerbonne,et al.  Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT , 2007, The Journal of physiology.

[6]  Karen Birmingham,et al.  the heart , 2002, Nature.

[7]  J. Nerbonne,et al.  Targeted Deletion of Kv4.2 Eliminates Ito,f and Results in Electrical and Molecular Remodeling, With No Evidence of Ventricular Hypertrophy or Myocardial Dysfunction , 2005, Circulation research.

[8]  G. Jennings,et al.  DIFFERENCES BETWEEN PATHOLOGICAL AND PHYSIOLOGICAL CARDIAC HYPERTROPHY: NOVEL THERAPEUTIC STRATEGIES TO TREAT HEART FAILURE , 2007, Clinical and experimental pharmacology & physiology.

[9]  C. Romanin,et al.  Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex. , 2007, Cardiovascular research.

[10]  G. Steinbeck,et al.  Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. , 1996, Circulation.

[11]  Weinong Guo,et al.  Four Kinetically Distinct Depolarization-activated K+ Currents in Adult Mouse Ventricular Myocytes , 1999, The Journal of general physiology.

[12]  Ming Lei,et al.  Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart , 2005, The Journal of physiology.

[13]  J. Nerbonne,et al.  Heterogeneous expression of repolarizing, voltage‐gated K+ currents in adult mouse ventricles , 2004, The Journal of physiology.

[14]  P. Watson,et al.  Biochemical mechanisms of cardiac hypertrophy. , 1987, Annual review of physiology.

[15]  R. Hannan,et al.  Cardiac hypertrophy: A matter of translation , 2003, Clinical and experimental pharmacology & physiology.

[16]  H. Ehmke,et al.  Regional alterations of repolarizing K+ currents among the left ventricular free wall of rats with ascending aortic stenosis , 2001, The Journal of physiology.

[17]  J. Nerbonne,et al.  Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 alpha subunit. , 1999, Circulation research.

[18]  D. Kass,et al.  Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. , 1996, Circulation research.

[19]  T. Schwarz,et al.  The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes , 2001, The Journal of physiology.

[20]  A. Maguy,et al.  Expression, regulation and role of the MAGUK protein SAP-97 in human atrial myocardium. , 2002, Cardiovascular research.

[21]  G. Chejfec.  Robbins Pathologic Basis of Disease , 2009 .

[22]  A. Lopatin,et al.  Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability. , 2003, Journal of molecular and cellular cardiology.

[23]  R. Kerber,et al.  Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. , 2000, Circulation.

[24]  P Hunter,et al.  GENE EXPRESSION OF STRETCH‐ACTIVATED CHANNELS AND MECHANOELECTRIC FEEDBACK IN THE HEART , 2006, Clinical and experimental pharmacology & physiology.

[25]  Jochen Rose,et al.  Molecular correlates of altered expression of potassium currents in failing rabbit myocardium. , 2005, American journal of physiology. Heart and circulatory physiology.

[26]  S. Nattel,et al.  Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. , 2007, Physiological reviews.

[27]  J. Ross,et al.  A Defect in the Kv Channel-Interacting Protein 2 (KChIP2) Gene Leads to a Complete Loss of I to and Confers Susceptibility to Ventricular Tachycardia , 2001, Cell.

[28]  J. Nerbonne,et al.  Role of Heteromultimers in the Generation of Myocardial Transient Outward K+ Currents , 2002, Circulation research.

[29]  A. A. Armoundas,et al.  Electrical and structural remodeling of the failing ventricle. , 2001, Pharmacology & therapeutics.

[30]  J. Ross,et al.  Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Ross,et al.  Transthoracic echocardiography in models of cardiac disease in the mouse. , 1996, Circulation.

[32]  P. Anthony.  Robbins' Pathologic Basis of Disease , 1990 .

[33]  Xianlin Han,et al.  Transgenic Expression of Fatty Acid Transport Protein 1 in the Heart Causes Lipotoxic Cardiomyopathy , 2005, Circulation research.

[34]  R. Taylor,et al.  Increased protein synthesis and degradation in the dog heart during thyroxine administration. , 1983, Journal of molecular and cellular cardiology.

[35]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[36]  H. Duff,et al.  In vivo temporal and spatial distribution of depolarization and repolarization and the illusive murine T wave , 2004, The Journal of physiology.

[37]  Stanley Nattel,et al.  Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts , 2004, The Journal of physiology.

[38]  G. Mitchell,et al.  Measurement of heart rate and Q-T interval in the conscious mouse. , 1998, American journal of physiology. Heart and circulatory physiology.

[39]  Janet L. Johnstone,et al.  Remodeling of Outward K+ Currents in Pressure‐Overload Heart Failure , 2007, Journal of cardiovascular electrophysiology.

[40]  K. Chien,et al.  Erratum: Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy (Proc. Natl. Acad. Sci. USA (September 1991) 88 (8277-8281)) , 1991 .

[41]  Ton Feuth,et al.  Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes , 2005, Laboratory Investigation.

[42]  G. Steinbeck,et al.  Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. , 1998, Circulation.

[43]  V. Shusterman,et al.  Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine-Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation , 2001, Circulation research.