Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc
| Autor: | Denise Hilfiker-Kleiner, Christian Willenbockel, Tibor Kempf, Sandra C. Gross, Pico Caroni, Marian Naguib, Joerg Heineke, Robert A. Kaiser, Hartmut Ruetten, Helmut Drexler, Theresia Kraft, Arnd Schaefer, Kai C. Wollert, Jeffery D. Molkentin |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Genetically modified mouse
Sarcomeres medicine.medical_specialty Systole Myocardial Infarction Muscle Proteins Vasodilation Biology Sarcomere Ventricular Function Left Mice Internal medicine medicine Animals Ventricular remodeling CSRP3 Mice Knockout Multidisciplinary Ventricular Remodeling Calcineurin NFAT Heart Biological Sciences LIM Domain Proteins medicine.disease Mice Mutant Strains Disease Models Animal Endocrinology Echocardiography Heart failure Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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