Cardiac aging: Send in the vinculin reinforcements

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Science Translational Medicine  17 Jun 2015:
Vol. 7, Issue 292, pp. 292fs26
DOI: 10.1126/scitranslmed.aab3391


Integration of multiple analytical approaches across three species—fly, rat, and nonhuman primate—reveals additional roles for vinculin in cytoskeletal aging and cardiovascular disease (Kaushik et al., this issue).

Cardiovascular disease is the number one cause of death in the United States, and its incidence and severity are heightened with advanced age. According to the World Health Organization, an estimated 524 million people were 65 years of age or older in 2010. By 2050, this number is projected to triple, highlighting the need to better understand the cardiac remodeling processes that occur with age (1). Some mechanisms of cardiac remodeling may be compensatory and beneficial, keeping the heart functioning over our life span. Understanding these mechanisms could therefore allow for targeted interventions to prevent adverse cardiac aging in healthy patients, to improve function in heart failure patients, or to identify biomarkers of the aging heart. The cellular cytoskeleton has been implicated in the way cells sense and transmit forces, leading to changes in cardiac function, but its role in aging is unclear (2).

In this issue of Science Translational Medicine, Kaushik et al. integrate proteomic, biochemical, histological, and physiological approaches across several species to uncover a cardiac aging–induced cytoskeletal reorganization mechanism (3). Their data establish a conserved aging program in species of varying heart complexity that centers on the cytoskeletal protein vinculin and includes other mechanosensitive proteins to link cellular activity to whole-heart function.

Vinculin: At the heart of it all

Kaushik et al. showed that age-related increases in vinculin are conserved across humans, rhesus monkeys, rats, mice, and Drosophila (3). Vinculin localizes to integrin-mediated cell–matrix and cadherin-mediated cell-cell adhesions and serves as one of several interacting proteins involved in anchoring F-actin to the membrane. Increased age also correlates with increased incidence of diastolic dysfunction and increased passive stiffness in mice (4). Thus, Kaushik et al. hypothesized that vinculin accumulation with age may relate to changes in cortical stiffening and contractility.

The authors first performed a broad proteomic analysis of the left ventricle free wall in adult and aged monkeys and rats, focusing specifically on cytoskeletal proteins rather than extracellular (ECM) components. The network interactions of cardiomyopathy-associated proteins up-regulated with age in monkeys were generated by using a human genetic phenotype database, OMIM (Online Mendelian Inheritance in Man), to reveal potential points of intervention or therapeutic regulation.

In rats, vinculin accumulated preferentially at the intercalated discs (IDs), similar to what has been seen in humans with heart failure (5). Although this suggests that vinculin reinforces the cortical actin superstructure (Fig. 1), the mechanical properties were more easily studied in Drosophila melanogaster models (the fruit fly), which have diastolic restriction and cortical stiffening as they age and differ in mechanical performance according to fly strain. They found that cardiac-specific vinculin overexpression in young flies recapitulates age-related cortical stiffening and that the actin cytoskeleton likely plays a major role, as seen in rodents and monkeys.

Fig. 1 Mechanisms of cytoskeletal reinforcement.

Vinculin aids in anchoring myofibrils and facilitating longitudinal force transmission between myocytes. Advanced age is associated with increased levels of cardiac vinculin. Vinculin overexpression results in cytoskeletal reinforcement, causes myofibril reordering, and improves cardiac performance in flies. Further, cardiac vinculin overexpression extends life span. These findings demonstrate the potential role of vinculin overexpression as a beneficial cardiac aging response. Figure adapted from Kaushik et al. (3), with permission.


In healthy flies overexpressing vinculin, the authors noted increased myocardial shortening velocities and a concomitant increase in life span compared with that of controls. In flies with dysfunctional hearts (exhibiting knock down of cardiac myosin heavy chain), co-overexpression of vinculin partially rescued impaired contractility and extended life span. Together, these data suggest that vinculin reinforces the myocardial cytoskeleton and, in turn, positively influences contractility and prolongs life. Interestingly, in both aged rats and flies, vinculin was located primarily at the cell-cell junctions, where the authors hypothesize vinculin partly helps to anchor myofibrils and facilitate longitudinal force transmission between myocytes, implicating vinculin as an extrasarcomeric regulator of myocyte contractility and cardiac function (Fig. 1).

Benefit of multiple models

Kaushik et al. used three animal models—monkeys, rats, and Drosophila—applying the strength of each model to integrate complementary information across various scales in order to determine the effect of age on conserved cytoskeletal features and the role vinculin plays in regulating the cardiac remodeling process. A key factor that makes this approach work is that common variables were measured across models, which allowed results to be integrated.

Nonhuman primates, such as Rhesus monkeys, have the advantage of physiological, metabolic, and biochemical similarity to humans. For example, Rhesus monkeys develop insulin resistance, dyslipidemia, hypertension, and type II diabetes with adult-onset obesity comparable with what is observed in the clinic. In addition, the genome from the rhesus monkey shares ~93% of sequence homology with the human genome. Despite these strengths, the primate model requires specialized equipment, dedicated surgical facilities, and skilled personnel. In addition, the high research costs and low availability of genomic tools limit the potential for these studies to provide mechanistic insight.

Rodents are the most commonly used cardiovascular research animals, accounting for an estimated 90% of biomedical research use. Rats have cardiac physiology similar to that of humans, with ejection fraction and mean arterial pressure within the same ranges (6). More recent advances in genomic tools, including deletion and transgenic technology, have been developed for the rat, increasing its potential for mechanistic studies. In addition, rats are fairly easy to breed and are of relatively lower cost than larger animals.

Drosophila has recently become a preeminent model organism for cardiac research for several reasons: simplicity of handling, low cost, and availability of genetic methods and tools far exceed any other complex multicellular organism (7). The ability to perform large-scale genetic screening for disease progression genes makes Drosophila a strong model. In addition, isolation of the intact Drosophila heart preserves the cytoskeleton and myofilament lattice, which allows proficient examination of functional responses to mechanical stimulation. Researchers who choose to use Drosophila, however, need to consider two important limitations: the small size of the heart and the structural differences compared with the human cardiovascular system. The Drosophila heart consists of a tubular structure composed of a single layer of contractile cardiomyocytes with a prominent anterior region called the conical chamber. An echocardiogram technique has been developed based on optical coherence tomography to provide noninvasive, nondestructive images that are analogous to transthoracic echocardiography in humans and mice (8). Despite these limitations, small animal models are still considered the best tools for understanding the mechanisms of human cardiovascular disease (6).

No single animal model perfectly recreates the human disease state, and researchers select models that most likely yield insights into the research questions being queried. Kaushik et al. used a cooperative approach by integrating findings from proteomic and biochemical methods with physiology variables. In addition, by harnessing the strengths of more than one animal model, they were able to minimize the limitations of each to generate an optimal model. Studies that take this approach to merge genetic model systems with physiology, proteomics, bioinformatics, structural biology, and compound screening will provide an exciting framework for cardiovascular research and drug design (9).

Translational impact

The authors focused on conserved changes in the cardiac cytoskeleton that spanned three species, leading to mechanistic insight into the effect of aging on the cardiac cytoskeleton (Fig. 1) and establishing a database of results that will be useful for identifying therapeutic targets to slow or reverse cardiac aging (3). Proteomic methods were used to enrich for intracellular and cytoskeletal components, identifying vinculin as the main target of interest. Although the authors focused on vinculin, their proteomic compendium provides an array of therapeutic targets that could be investigated for treating heart failure and/or the aging—yet healthy—heart or for better understanding cardiac aging and identifying biomarkers (Fig. 1). For example, further examination of the upstream regulators of vinculin, such as α-catenin and protein kinase B, may provide crucial evidence into the molecular changes initiated by aging.

Advanced aging is associated with increased posttranslational modifications, and vinculin is a cytoskeletal protein that undergoes extensive posttranslational modification, including palmitoylation and myristoylation. How these modifications regulate vinculin functions in the diseased state remains unclear. Determining the effect of posttranslational modifications on the function of vinculin and identifying whether these changes are age-associated would better assess the potential of vinculin to serve as a biomarker of either aging or heart failure. Furthermore, previous studies have demonstrated an increase in age-amplified extracellular matrix (ECM) proteins, leading to excessive myocardial fibrosis, increased myocardial stiffness, and diastolic dysfunction (4). Rigid ECM is known to affect focal adhesion composition, including increased expression and activation of vinculin. Activated vinculin binds tightly to F-actin and perturbs overall cytoskeletal form and function in turn. Thus, the matrix remodeling process is thought to contribute to signaling events that regulate focal adhesion formation and cellular function (10).

Although many of these pathways can be followed, given the wealth of proteomic information from Kaushik et al., the mechanism of vinculin action in the human myocyte cytoskeleton is yet to be fully elucidated (Fig. 1). The authors relied on several different Drosophila strains to tease apart the contribution of vinculin to heart function, but clinically relevant metrics in patients and the association between vinculin and life span are unknown. Nevertheless, the conservation of vinculin at the heart of cardiac aging across three different animals generates continued interest in this molecule for treating the aging heart, opening doors to gene therapy as well as small-molecule, enzymatic, and microRNA regulators.


  1. Funding: We acknowledge support from NIH/National Heart, Lung, and Blood Institute (NHLBI) Health and Human Services Number 268201000036C (N01-HV-00244) for the San Antonio Cardiovascular Proteomics Center; NIH/NHLBI for HL075360 and HL051971; NIH/National Institute of General Medical Sciences for GM104357; and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award 5I01BX000505.
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