Faculty Collaboration Database

Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. J Am Coll Cardiol 2014 Dec 30;64(25):2765-76

Date

12/30/2014

Pubmed ID

25541130

Pubmed Central ID

PMC4279060

DOI

10.1016/j.jacc.2014.09.071

Scopus ID

2-s2.0-84919608962 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

BACKGROUND: Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.

OBJECTIVES: The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.

METHODS: Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (Mypn(WT/Q526X)) and homozygote mice harboring the human MYPN-Q529X mutation.

RESULTS: Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated Mypn(Q526X) protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers.

CONCLUSIONS: Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence of mutant Mypn(Q526X) protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in Mypn(WT/Q526X) hearts.

Author List

Huby AC, Mendsaikhan U, Takagi K, Martherus R, Wansapura J, Gong N, Osinska H, James JF, Kramer K, Saito K, Robbins J, Khuchua Z, Towbin JA, Purevjav E

MESH terms used to index this publication - Major topics in bold

Animals
Cardiomyopathy, Restrictive
Codon, Nonsense
Disease Models, Animal
Down-Regulation
Echoencephalography
Electrocardiography
Gene Knock-In Techniques
Heart Failure, Diastolic
Heterozygote
Homozygote
Humans
Magnetic Resonance Imaging
Mice
Muscle Proteins
Signal Transduction
Up-Regulation