SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.

Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.

[1]  K. Walley,et al.  S100A8 and S100A9 Mediate Endotoxin-Induced Cardiomyocyte Dysfunction via the Receptor for Advanced Glycation End Products , 2008, Circulation research.

[2]  Zhenguo Wu,et al.  JAK1–STAT1–STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts , 2007, The Journal of cell biology.

[3]  T. Hunt,et al.  Calcineurin is required to release Xenopus egg extracts from meiotic M phase. , 2007, Nature.

[4]  D. Kressler,et al.  Coactivators PGC-1β and SRC-1 Interact Functionally to Promote the Agonist Activity of the Selective Estrogen Receptor Modulator Tamoxifen* , 2007, Journal of Biological Chemistry.

[5]  G. Dorn,et al.  Sarcoplasmic Reticulum Calcium Overloading in Junctin Deficiency Enhances Cardiac Contractility but Increases Ventricular Automaticity , 2007, Circulation.

[6]  Ling Lu,et al.  Molecular Coupling of a Ca2+-Activated K+ Channel to L-Type Ca2+ Channels via α-Actinin2 , 2007 .

[7]  T. Furukawa,et al.  Potassium channel remodeling in cardiac hypertrophy. , 2006, Journal of molecular and cellular cardiology.

[8]  Maqc Consortium The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements , 2006, Nature Biotechnology.

[9]  A. Prinz,et al.  Effect of simulated I(to) on guinea pig and canine ventricular action potential morphology. , 2006, American journal of physiology. Heart and circulatory physiology.

[10]  G. Dorn,et al.  The Presence of Lys27 Instead of Asn27 in Human Phospholamban Promotes Sarcoplasmic Reticulum Ca2+-ATPase Superinhibition and Cardiac Remodeling , 2006, Circulation.

[11]  G. Dorn,et al.  A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Bollensdorff,et al.  Expression pattern of neuronal and skeletal muscle voltage‐gated Na+ channels in the developing mouse heart , 2005, Journal of Physiology.

[13]  M. Wellner,et al.  Cardiac gene expression profile in rats with terminal heart failure and cachexia. , 2005, Physiological genomics.

[14]  G. Bett,et al.  Computer model of action potential of mouse ventricular myocytes. , 2004, American journal of physiology. Heart and circulatory physiology.

[15]  S. Rosenkranz TGF-β1 and angiotensin networking in cardiac remodeling , 2004 .

[16]  J. Yates,et al.  Protein Trafficking and Anchoring Complexes Revealed by Proteomic Analysis of Inward Rectifier Potassium Channel (Kir2.x)-associated Proteins* , 2004, Journal of Biological Chemistry.

[17]  H. Reddy,et al.  Current Perspectives of Electrical Remodeling and Its Therapeutic Implications , 2004, Journal of cardiovascular pharmacology and therapeutics.

[18]  Mohamed Chahine,et al.  Modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by protein kinase A and protein kinase C. , 2004, Journal of neurophysiology.

[19]  C. J. Huang,et al.  The enhancement of nuclear receptor transcriptional activation by a mouse actin-binding protein, alpha actinin 2. , 2004, Journal of molecular endocrinology.

[20]  D. Bers,et al.  Cellular basis of triggered arrhythmias in heart failure. , 2004, Trends in cardiovascular medicine.

[21]  E. Kranias,et al.  Calcium: Phospholamban: a crucial regulator of cardiac contractility , 2003, Nature Reviews Molecular Cell Biology.

[22]  D. Dorris,et al.  Oligodeoxyribonucleotide probe accessibility on a three-dimensional DNA microarray surface and the effect of hybridization time on the accuracy of expression ratios , 2003, BMC biotechnology.

[23]  G. Pavlath,et al.  IL-4 Acts as a Myoblast Recruitment Factor during Mammalian Muscle Growth , 2003, Cell.

[24]  Isaac S Kohane,et al.  Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Gambaryan,et al.  Interaction of the Plasma Membrane Ca2+ Pump 4b/CI with the Ca2+/Calmodulin-dependent Membrane-associated Kinase CASK* , 2003, The Journal of Biological Chemistry.

[26]  Ulrike Mende,et al.  Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban , 2003, Science.

[27]  S. Wahl,et al.  Dysregulation of IFN-γ Signaling Pathways in the Absence of TGF-β1 , 2002, The Journal of Immunology.

[28]  Andrew N. Carr,et al.  Structural and functional implications of the phospholamban hinge domain: impaired SR Ca2+ uptake as a primary cause of heart failure. , 2002, Cardiovascular research.

[29]  F. Verdonck,et al.  Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? , 2002, Cardiovascular research.

[30]  S. Lin-Chao,et al.  Association of the growth-arrest-specific protein Gas7 with F-actin induces reorganization of microfilaments and promotes membrane outgrowth. , 2002, Experimental cell research.

[31]  Andrew N. Carr,et al.  Gender influences on sarcoplasmic reticulum Ca2+-handling in failing human myocardium. , 2001, Journal of molecular and cellular cardiology.

[32]  Joseph A. Hill,et al.  Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy* , 2001, The Journal of Biological Chemistry.

[33]  R. Ramirez,et al.  The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium. , 2001, Journal of molecular and cellular cardiology.

[34]  Wolzt,et al.  World Medical Association Declaration of Helsinki , 2000, International Journal of Pharmaceutical Medicine.

[35]  B. Hoit,et al.  Cardiac-specific Overexpression of a Superinhibitory Pentameric Phospholamban Mutant Enhances Inhibition of Cardiac Functionin Vivo * , 2000, The Journal of Biological Chemistry.

[36]  M. Sheng,et al.  Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2 , 2000, Nature.

[37]  K. Frank,et al.  Phospholamban and cardiac contractility , 2000, Annals of medicine.

[38]  Philippe Soriano,et al.  Shroom, a PDZ Domain–Containing Actin-Binding Protein, Is Required for Neural Tube Morphogenesis in Mice , 1999, Cell.

[39]  E. Kranias,et al.  Transgenic Approaches to Define the Functional Role of Dual Site Phospholamban Phosphorylation* , 1998, The Journal of Biological Chemistry.

[40]  J. Caldwell,et al.  Interaction of Muscle and Brain Sodium Channels with Multiple Members of the Syntrophin Family of Dystrophin-Associated Proteins , 1998, The Journal of Neuroscience.

[41]  J. Harrer,et al.  Application of the immunoblot technique for quantitation of protein levels in cardiac homogenates. , 1995, BioTechniques.

[42]  W. Catterall,et al.  Modulation of cardiac Na+ channels expressed in a mammalian cell line and in ventricular myocytes by protein kinase C. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Fleischer,et al.  The nature of the modulation of Ca2+ transport as studied by reconstitution of cardiac sarcoplasmic reticulum. , 1986, The Journal of biological chemistry.

[44]  Donald M. Bers,et al.  Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure , 2002, Basic Research in Cardiology.

[45]  Y. Yazaki,et al.  Loss of WT1 function leads to ectopic myogenesis in Wilms' tumour , 1998, Nature Genetics.

[46]  A. Katz,et al.  Phosphorylation of the sarcoplasmic reticulum and sarcolemma. , 1982, Annual review of physiology.