Abstract 13429: Restrictive Cardiomyopathy Due to Myopalladin Nonsense Q529x Mutation is Associated with Erk1/2 and Carp Down-Regulation
Background: Restrictive cardiomyopathy (RCM), a rare form of cardiomyopathy, has the worst prognosis, particularly in children. Although the mechanism(s) responsible for the clinical features and poor prognosis in RCM is thought due to restrictive physiology (RP) caused by diastolic dysfunction and resultant myocardial stiffness and fibrosis, the mechanism is unclear. Myopalladin (MYPN) is a nodal messenger molecule that transmits stretch-signaling from the Z-disk to the nucleus in cardiomyocytes. A novel human nonsense mutation (Q529X MYPN), truncating the nebulette-α-actinin domain of MYPN, has been shown to cause familial restrictive cardiomyopathy (FRCM). We studied the causative mechanisms using a knock-in mouse model.
Methods: A MYPN-Q529X knock-in (MYPNWT/Q529X) mouse model was generated via gene targeting. Functional and morphohistological, as well as molecular and gene expression studies, were performed in wild-type and mutant mice.
Results: Mutant heterozygous MYPNWT/Q529X mice developed echo signs of RP, noted by increased E/A ratios with preserved systolic function without dilated atria or mitral valve regurgitation at 12 weeks of age. Heart failure markers ANP, BNP and β-MHC were increased. Histologically, interstitial and perivascular fibrosis without overt hypertrophic remodeling was observed in the heart. CTGF, an activator of fibroblasts, was increased in MYPNWT/Q529X mice though collagens (col1α1, col3α1) and TGFβ1 were not upregulated. Protein analysis revealed down-regulation of the MYPN binding partner CARP/ARKD1, and reduced phosphorylation of MEKK1/2 and ERK1/2, irrespective to normal ERK1/2 levels.
Conclusions: The nonsense mutation Q529X-MYPN diminishes ERK1/2 phosphorylation and CARP expression augmenting CTGF production in MYPNWT/Q529X hearts. Reduced phospho-ERK1/2 and MEKK1/2 appears to cause cardiac fibrosis and FRCM due to abbreviated mechanotransduction via disturbed nebulette-α-actinin-actin interactions with MYPN at the Z-discs.
- © 2012 by American Heart Association, Inc.