title: Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart.
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.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kaushik
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Spenlehauer
authors.affiliation: Biomedical Sciences Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ayla O
authors.initials: AO
authors.lastname: Sessions
authors.affiliation: Department of Biology, Heart Institute, and Molecular Biology Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Trujillo
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fuhrmann
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Zongming
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Advanced Clinical Biosystems Research Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Venkatraman
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Pohl
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tuler
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.affiliation: Development and Aging Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ocorr
authors.affiliation: Development and Aging Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.affiliation: Department of Biology, Heart Institute, and Molecular Biology Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Sanford I
authors.initials: SI
authors.lastname: Bernstein
authors.affiliation: 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.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. acammar3@jhmi.edu aengler@ucsd.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cammarato
authors.affiliation: 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.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D003599:Cytoskeleton / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology; D005260:Female; D005838:Genotype; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D020543:Proteome / Q000378:metabolism; D051381:Rats; D020257:Ventricular Remodeling; D016596:Vinculin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D020543:Proteome; D016596:Vinculin