Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc.
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.
Heineke
Joerg
J
Department of Cardiology, Hanover Medical School, 30625 Hanover, Germany.
Ruetten
Hartmut
H
Willenbockel
Christian
C
Gross
Sandra C
SC
Naguib
Marian
M
Schaefer
Arnd
A
Kempf
Tibor
T
Hilfiker-Kleiner
Denise
D
Caroni
Pico
P
Kraft
Theresia
T
Kaiser
Robert A
RA
Molkentin
Jeffery D
JD
Drexler
Helmut
H
Wollert
Kai C
KC
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*
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3; D019703:Calcineurin