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Sci Transl Med. 2015 Jun 17;7(292):292ra99. doi: 10.1126/scitranslmed.aaa5843.

Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart.

Author information

1
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
2
Biomedical Sciences Program, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Biology, Heart Institute, and Molecular Biology Institute, San Diego State University, San Diego, CA 92182, USA.
4
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
5
Advanced Clinical Biosystems Research Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
6
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
7
Development and Aging Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
8
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Advanced Clinical Biosystems Research Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
9
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. acammar3@jhmi.edu aengler@ucsd.edu.
10
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. Biomedical Sciences Program, University of California, San Diego, La Jolla, CA 92093, USA. Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. acammar3@jhmi.edu aengler@ucsd.edu.

Abstract

The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. A broad array of potential therapeutic targets and regulators of age-associated modifications, specifically for vinculin, are presented. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts.

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PMID:
26084806
PMCID:
PMC4507505
DOI:
10.1126/scitranslmed.aaa5843
[Indexed for MEDLINE]
Free PMC Article

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