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Cited by 46Cardiomyopathy and Myosin StudiesSignaling Pathways in DiseaseProtein Tyrosine Phosphatases

Dilated cardiomyopathy in transgenic mice expressing a mutant A subunit of protein phosphatase 2A

Brewis, Neil, Ohst, Kim, Fields, Katherine, Rapacciuolo, Antonio, Chou, Danny, Bloor, Colin, Dillmann, Wolfgang, Rockman, Howard +1 more·2000·American Journal of Physiology-Heart and Circulatory Physiology
DOI 10.1152/ajpheart.2000.279.3.h1307
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Abstract

The protein phosphatase 2A (PP2A) holoenzyme consists of a catalytic subunit, C, and two regulatory subunits, A and B. The PP2A core enzyme is composed of subunits A and C. Both the holoenzyme and the core enzyme are similarly abundant in heart tissue. Transgenic mice were generated expressing high levels of a dominant negative mutant of the A subunit (A delta 5) in the heart, skeletal muscle, and smooth muscle that competes with the endogenous A subunit for binding the C subunit but does not bind B subunits. We found that the ratio of core enzyme to holoenzyme was increased in A delta 5-expressing hearts. Importantly, already at day 1 after birth, A delta 5-transgenic mice had an increased heart weight-to-body weight ratio that persisted throughout life. Echocardiographic analysis of A delta 5-transgenic hearts revealed increased end-diastolic and end-systolic dimensions and decreased fractional shortening. In addition, the thickness of the septum and of the left ventricular posterior wall was significantly reduced. On the basis of these findings, we consider the heart phenotype of A delta 5-transgenic mice to be a form of dilated cardiomyopathy that frequently leads to premature death.

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  • At 3-4 months, 25% of AΔ5 mice died within a few weeks after showing extremely enlarged hearts and increased respiratory rates.

    “At 3-4 months, 25% of these mice died within a few weeks after showing extremely enlarged hearts and increased respiratory rates [65].”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [65]

  • Muscle-specific expression of a dominant negative Aα subunit lacking HEAT-repeat 5 caused dilated cardiomyopathy from P1 onwards.

    “Muscle-specific expression of a dominant negative Aα subunit lacking HEAT-repeat 5 (AΔ5), which mediates important interactions with all B-type subunits, also resulted in dilated cardiomyopathy from P1 onwards.”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [65]

  • The AΔ5 phenotype included enlarged heart, impaired left ventricle function, reduced septum thickness, reduced left ventricular posterior wall thickness, and increased β-MHC transcripts.

    “This phenotype was characterized by an enlarged heart, impaired left ventricle function, reduced septum thickness, reduced thickness of the left ventricular posterior wall, and increased expression of β-MHC transcripts [65].”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [65]

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Authors
Brewis, N., Ohst, K., Fields, K., Rapacciuolo, A., Chou, D., Bloor, C., Dillmann, W., Rockman, H., & Walter, G.
Affiliations
  • Department of Pathology and
  • Duke Medical Center (US)
  • University of California San Diego (US)
ORCID
Venue
American Journal of Physiology-Heart and Circulatory Physiology
Publisher
American Physiological Society
Published
2000-09-01
Volume
279
Issue
3
Pages
H1307-H1318
ISSN
  • 0363-6135 (ISSN-L)
  • 1522-1539
DOI
10.1152/ajpheart.2000.279.3.h1307
OpenAlex
W2403198344
Cited by
46
References
46
Citations by year
2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 3
FWCI
2.22
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (2r01hl061558-07)
  • National Heart, Lung, and Blood Institute (HL-61558)
  • National Cancer Institute (CA-36111, R01CA036111)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
dilated cardiomyopathy, protein phosphatase 2A, dominant-negative mutant, transgenic mice, cardiac hypertrophy, heart failure, cardiac contractility, PP2A holoenzyme, premature mortality
MeSH terms
Animals, Body Weight, Cardiomyopathy, Dilated, Echocardiography, Exons, Genes, Dominant, Mice, Transgenic, Muscle, Smooth, Myocardium, Organ Specificity, Organ Size, Phosphoprotein Phosphatases, Protein Binding, Gene Expression, Mutagenesis, Site-Directed, Sequence Deletion, Muscle, Skeletal, Transgenes, Holoenzymes, Mice, Protein Phosphatase 2

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