Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc

摘要: Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause for heart failure. Molecular modifiers of the process remain poorly defined. Patients with failure MI have reduced LV expression levels muscle LIM protein (MLP), component sarcomeric Z-disk that involved in integration stress signals cardiomyocytes. By using heterozygous MLP mutant (MLP+/—) mice, we explored role post-MI remodeling. dimensions and function were similar sham-operated WT MLP+/— mice. After MI, however, mice displayed more pronounced dilatation systolic dysfunction decreased survival compared indicating predispose to adverse was associated thickening but enhanced elongation Activation stress-responsive, prohypertrophic calcineurin–nuclear factor activated T-cells (NFAT) signaling pathway as shown by blunted transcriptional activation NFAT cardiomyocytes isolated from MLP+/—/NFAT-luciferase reporter gene transgenic Calcineurin colocalized at displaced essential calcineurin anchorage Z-disk. In vitro assays down-regulated confirmed required stress-induced calcineurin–NFAT activation. Our study reveals link between sensor indicates MLP–calcineurin predisposes MI.