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Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase

Lookup NU author(s): Professor Bob Anderson

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Abstract

Under pressure overload, initial adaptive hypertrophy of the heart is followed by cardiomyocyte elongation, reduced contractile force, and failure. The mechanisms governing the transition to failure are not fully understood. Pressure overload reduced cardiac myosin light chain kinase (cMLCK) by similar to 80% within 1 week and persists. Knockdown of cMLCK in cardiomyocytes resulted in reduced cardiac contractility and sarcomere disorganization. Thus, we hypothesized that acute reduction of cMLCK may be causative for reduced contractility and cardiomyocyte remodelling during the transition from compensated to decompensated cardiac hypertrophy.To mimic acute cMLCK reduction in adult hearts, the floxed-Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3(flox/flox)/merCremer mice (Mylk3-KO), and compared with two control mice (Mylk3(flox/flox) and Mylk3(+/+)/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). In Mylk3-KO mice, reduction of cMLCK protein was evident by 4 days, with a decline to below the level of detection by 6 days. By 7 days, these mice exhibited heart failure, with reduction of fractional shortening compared with those in two control groups (19.8 vs. 28.0% and 27.7%). Severely convoluted cardiomyocytes with sarcomeric disorganization, wavy fibres, and cell death were demonstrated in Mylk3-KO mice. The cardiomyocytes were also unable to thicken adaptively to pressure overload.Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization.

Publication metadata

Author(s): Massengill MT, Ashraf HM, Chowdhury RR, Chrzanowski SM, Kar J, Warren SA, Walter GA, Zeng HD, Kang BH, Anderson RH, Moss RL, Kasahara H

Publication type: Article

Publication status: Published

Journal: Cardiovascular Research

Year: 2016

Volume: 111

Issue: 1

Pages: 34-43

Print publication date: 01/07/2016

Online publication date: 29/03/2016

Acceptance date: 17/03/2016

ISSN (print): 0008-6363

ISSN (electronic): 1755-3245

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/cvr/cvw069

DOI: 10.1093/cvr/cvw069

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