The Transgenic Expression of Highly Inhibitory Monomeric Forms of Phospholamban in Mouse Heart Impairs Cardiac Contractility

Transgenic mice were generated with cardiac-specific overexpression of the monomeric, dominant-acting, superinhibitory L37A and I40A mutant forms of phospholamban (PLN), and their phenotypes were compared with wild-type (wt) mice or 2-fold overexpressors of wt PLN (wtOE). The level of PLN monomer in...

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Veröffentlicht in:The Journal of biological chemistry 2000-05, Vol.275 (20), p.14985-14991
Hauptverfasser: Zvaritch, Elena, Backx, Peter H., Jirik, Frank, Kimura, Yoshihiro, de Leon, Stella, Schmidt, Albrecht G., Hoit, Brian D., Lester, J.William, Kranias, Evangelia G., MacLennan, David H.
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container_end_page 14991
container_issue 20
container_start_page 14985
container_title The Journal of biological chemistry
container_volume 275
creator Zvaritch, Elena
Backx, Peter H.
Jirik, Frank
Kimura, Yoshihiro
de Leon, Stella
Schmidt, Albrecht G.
Hoit, Brian D.
Lester, J.William
Kranias, Evangelia G.
MacLennan, David H.
description Transgenic mice were generated with cardiac-specific overexpression of the monomeric, dominant-acting, superinhibitory L37A and I40A mutant forms of phospholamban (PLN), and their phenotypes were compared with wild-type (wt) mice or 2-fold overexpressors of wt PLN (wtOE). The level of PLN monomer in cardiac microsomes was increased 11–13-fold, and the apparent affinity of the sarco(endo)plasmic reticulum Ca2+-ATPase for Ca2+ was decreased from pCa 6.22 in wt or 6.12 in wtOE to 5.81 in L37A and 5.72 in I40A. Basal physiological parameters, measured in isolated myocytes, indicated a significant reduction in the rates of shortening (+dL/dt) and relengthening (−dL/dt). Hemodynamic measurements indicated that peak systolic pressure was unaffected but that pressure changes (+dP/dt and −dP/dt) were lowered significantly in both mutant lines, and relaxation time (τ) was also lengthened significantly. Echocardiography for both mutants showed depressed systolic function and an increase in left ventricular mass of over 1.4-fold. Significant decreases in left ventricular shortening fraction and velocity of circumferential shortening and increases in ejection time were corrected by isoproterenol. The use of antibodies specific against Ser16- and Thr17-PLN peptides showed that phosphorylation of both pentameric and monomeric PLN were increased between 1.2- and 2.4-fold in both the L37A and I40A lines but not in the wtOE line. These observations show that overexpression of superinhibitory mutant forms of PLN causes depression of contractile parameters with induction of cardiac hypertrophy, as assessed with echocardiography.
doi_str_mv 10.1074/jbc.275.20.14985
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The level of PLN monomer in cardiac microsomes was increased 11–13-fold, and the apparent affinity of the sarco(endo)plasmic reticulum Ca2+-ATPase for Ca2+ was decreased from pCa 6.22 in wt or 6.12 in wtOE to 5.81 in L37A and 5.72 in I40A. Basal physiological parameters, measured in isolated myocytes, indicated a significant reduction in the rates of shortening (+dL/dt) and relengthening (−dL/dt). Hemodynamic measurements indicated that peak systolic pressure was unaffected but that pressure changes (+dP/dt and −dP/dt) were lowered significantly in both mutant lines, and relaxation time (τ) was also lengthened significantly. Echocardiography for both mutants showed depressed systolic function and an increase in left ventricular mass of over 1.4-fold. Significant decreases in left ventricular shortening fraction and velocity of circumferential shortening and increases in ejection time were corrected by isoproterenol. The use of antibodies specific against Ser16- and Thr17-PLN peptides showed that phosphorylation of both pentameric and monomeric PLN were increased between 1.2- and 2.4-fold in both the L37A and I40A lines but not in the wtOE line. 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The use of antibodies specific against Ser16- and Thr17-PLN peptides showed that phosphorylation of both pentameric and monomeric PLN were increased between 1.2- and 2.4-fold in both the L37A and I40A lines but not in the wtOE line. These observations show that overexpression of superinhibitory mutant forms of PLN causes depression of contractile parameters with induction of cardiac hypertrophy, as assessed with echocardiography.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>10809743</pmid><doi>10.1074/jbc.275.20.14985</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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subjects Amino Acid Substitution
Animals
Blood Pressure
Calcium - metabolism
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Calcium-Transporting ATPases - metabolism
Echocardiography
Hemodynamics
Major Histocompatibility Complex
Mice
Mice, Transgenic
Mutagenesis, Site-Directed
Myocardial Contraction - physiology
Myocardium - metabolism
Phospholamban
Point Mutation
Rabbits
Sarcoplasmic Reticulum - enzymology
Systole
Ventricular Function, Left
title The Transgenic Expression of Highly Inhibitory Monomeric Forms of Phospholamban in Mouse Heart Impairs Cardiac Contractility
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