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Investigations into the sarcomeric protein and Ca2+-regulation abnormalities underlying hypertrophic cardiomyopathy in cats (felix catus)

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Title: Investigations into the sarcomeric protein and Ca2+-regulation abnormalities underlying hypertrophic cardiomyopathy in cats (felix catus)
Authors: Messer, AE
Chan, WS
Daley, A
Copeland, O
Marston, SB
Connolly, D
Item Type: Journal Article
Abstract: Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model.
Issue Date: 8-Jun-2017
Date of Acceptance: 12-May-2017
URI: http://hdl.handle.net/10044/1/48573
DOI: https://dx.doi.org/10.3389/fphys.2017.00348
ISSN: 1664-042X
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Physiology
Volume: 8
Copyright Statement: © 2017 Messer, Chan, Daley, Copeland, Marston and Connolly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: RG/11/20/29266
Keywords: Science & Technology
Life Sciences & Biomedicine
Physiology
Felix catus
Ragdoll cat
hypertrophic cardiomyopathy
cardiac muscle
Ca2+ regulation
troponin
phosphorylation
uncoupling/recoupling
TROPONIN-I PHOSPHORYLATION
HUMAN HEART-MUSCLE
MAINE COON CATS
APPARENTLY HEALTHY CATS
HUMAN-DISEASE
ANIMAL-MODEL
RAGDOLL CATS
C MUTATION
SPHYNX CAT
ASSOCIATION
Publication Status: Published
Article Number: 348
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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