Details

Autor(en) / Beteiligte

• Heineke, Joerg
• Ruetten, Hartmut
• Willenbockel, Christian
• Gross, Sandra C.
• Naguib, Marian
• Schaefer, Arnd
• Kempf, Tibor
• Hilfiker-Kleiner, Denise
• Caroni, Pico
• Kraft, Theresia
• Kaiser, Robert A.
• Molkentin, Jeffery D.
• Drexler, Helmut
• Wollert, Kai C.
• Ignarro, Louis J.

Titel

Attenuation of Cardiac Remodeling after Myocardial Infarction by Muscle LIM Protein-Calcineurin Signaling at the Sarcomeric Z-Disc

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2005-02, Vol.102 (5), p.1655-1660

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.