Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase
Autor: | Glenn A. Walter, Hideko Kasahara, Sonisha Warren, Stephen M. Chrzanowski, Robert H. Anderson, Byung-Ho Kang, Hassan Ashraf, Jeena Kar, Michael T. Massengill, Huadong Zeng, Richard L. Moss, Rajib Chowdhury |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Pressure overload medicine.medical_specialty Physiology business.industry Cardiac myocyte medicine.disease Sarcomere Muscle hypertrophy Contractility 03 medical and health sciences 030104 developmental biology Atrophy Endocrinology Cardiac Myosins Physiology (medical) Internal medicine Heart failure Medicine Cardiology and Cardiovascular Medicine business |
Zdroj: | Cardiovascular Research. 111:34-43 |
ISSN: | 1755-3245 0008-6363 |
DOI: | 10.1093/cvr/cvw069 |
Popis: | Aims 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 ∼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. Methods and results To mimic acute cMLCK reduction in adult hearts, the floxed- Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3flox/flox / merCremer mice ( Mylk3-KO ), and compared with two control mice ( Mylk3flox/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. Conclusion 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. |
Databáze: | OpenAIRE |
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