title: Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc.
abstract: Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause for heart failure. Molecular modifiers of the remodeling process remain poorly defined. Patients with heart failure after MI have reduced LV expression levels of muscle LIM protein (MLP), a component of the sarcomeric Z-disk that is involved in the integration of stress signals in cardiomyocytes. By using heterozygous MLP mutant (MLP+/-) mice, we explored the role of MLP in post-MI remodeling. LV dimensions and function were similar in sham-operated WT and MLP+/- mice. After MI, however, MLP+/- mice displayed more pronounced LV dilatation and systolic dysfunction and decreased survival compared with WT mice, indicating that reduced MLP levels predispose to adverse LV remodeling. LV dilatation in MLP+/- mice was associated with reduced thickening but enhanced elongation of cardiomyocytes. Activation of the stress-responsive, prohypertrophic calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP+/- mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP+/-/NFAT-luciferase reporter gene transgenic mice. Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the Z-disk in MLP+/- mice, indicating that MLP is essential for calcineurin anchorage to the Z-disk. In vitro assays in cardiomyocytes with down-regulated MLP confirmed that MLP is required for stress-induced calcineurin-NFAT activation. Our study reveals a link between the stress sensor MLP and the calcineurin-NFAT pathway at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP-calcineurin signaling predisposes to adverse remodeling after MI.
authors.affiliation: Department of Cardiology, Hanover Medical School, 30625 Hanover, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heineke
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
authors.forename: Christian
authors.initials: C
authors.lastname: Willenbockel
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Gross
authors.forename: Marian
authors.initials: M
authors.lastname: Naguib
authors.forename: Arnd
authors.initials: A
authors.lastname: Schaefer
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Pico
authors.initials: P
authors.lastname: Caroni
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kaiser
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D004195:Disease Models, Animal; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D012518:Sarcomeres / Q000502:physiology* / Q000648:ultrastructure; D015398:Signal Transduction; D013599:Systole; D014664:Vasodilation; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3; D019703:Calcineurin