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

Gaurav Kaushik, Alice Spenlehauer, Ayla O. Sessions, Adriana S. Trujillo, Alexander Fuhrmann, Zongming Fu, Vidya Venkatraman, Danielle Pohl, Jeremy Tuler, Mingyi Wang, Edward G. Lakatta, Karen Ocorr, Rolf Bodmer, Sanford I. Bernstein, Jennifer E. Van Eyk, Anthony Cammarato, Adam J. Engler

Research output: Contribution to journalArticlepeer-review

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 myosindeficient 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.

Original languageEnglish (US)
Article number292ra99
JournalScience translational medicine
Volume7
Issue number292
DOIs
StatePublished - Jun 17 2015

ASJC Scopus subject areas

  • Medicine(all)

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