title: Nuclear targeting of Akt enhances ventricular function and myocyte contractility.
abstract: Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca2+-ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho-protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart.
authors.affiliation: Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Alessandro
authors.initials: A
authors.lastname: Boni
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Padin-Iruegas
authors.forename: Tymoteusz J
authors.initials: TJ
authors.lastname: Kajstura
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiore
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Edmund H
authors.initials: EH
authors.lastname: Sonnenblick
authors.forename: Ezio
authors.initials: E
authors.lastname: Musso
authors.forename: Steve R
authors.initials: SR
authors.lastname: Houser
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012518:Sarcomeres / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000502:physiology; D016276:Ventricular Function; D000099211:Phospholamban
chemical_list: D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D051057:Proto-Oncogene Proteins c-akt; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban