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June 18, 2015

Protein Keeps Aging Heart Young at Heart

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    The human heart, which generates billions of beats over a lifetime, doesn’t succumb to aging as quickly as you might expect. It keeps going and going, notwithstanding the sluggish pace of heart cell renewal, by squeezing the most out of its existing allotment of cells. But how? The heart, it turns out, benefits from gene expression changes that make it possible for heart cells to remodel themselves.

    One gene expression change in particular appears to account for greatly improved contractile function in heart cells. This change, which leads to a relative abundance of the protein vinculin, has been studied in the aging hearts of fruit flies, rats, and monkeys. And a new study has determined that flies genetically programmed to express elevated levels of vinculin can live significantly longer—150% longer—than normal fruit flies.

    This result appeared June 17 in Science Translational Medicine, in an article entitled “Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart.” The article, submitted by scientists representing the University of California, San Diego, Johns Hopkins University, and other institutions, noted that “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.”

    The scientists found that vinculin tends to accumulate in the aging hearts of multiple species, not just flies, but also rats and monkeys. In addition, the scientists noted that vinculin—a protein known for its role in maintaining the cell’s backbone, or cytoskeleton—accumulates in human hearts.

    “More than 80% of protein groups found in flies, including vinculin network proteins, are similar to those found in rats and monkeys,” said Gaurav Kaushik, lead author on the study, who contributed to the project as a bioengineering Ph.D. student in the laboratory of Adam Engler, Ph.D., at UC San Diego. “We chose to focus on the proteins that naturally increase in expression in the aging hearts of flies, rats, and monkeys.”

    "We wanted to know if vinculin was a rogue player or more of an innocent bystander in the development of heart disease and age-related heart failure," added Anthony Cammarato, Ph.D., co-principal investigator. "Turns out, vinculin is a good guy, the body's way of slowing down the decline of one of its most vital organs as it grows old."

    “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,” wrote the authors in Science Translational Medicine. “Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging.”

    When the researchers compared cardiac cells obtained from rats of different ages, they found that tissues from old animals showed notable clustering of vinculin in the cell junctions, a pattern the team also observed in fruit flies. That pattern appears to allow vinculin to boost transmission of mechanical force from cell to cell and enhance overall heart contraction.

    The scientists also compared several strains of flies, including a strain with normally functioning vinculin genes and one naturally deficient in vinculin. Examining cardiac muscle cells under a microscope, the researchers noticed marked differences between the groups. The cardiac cells of flies with normal vinculin accumulation got smaller with age and showed the characteristic vinculin clustering around the periphery of the cell and along the intercellular bridges.

    When researchers induced genes in vinculin-deficient flies to crank out more of the protein, their heart cells quickly shrank in size and developed the same distinctive vinculin clustering around the border seen in cells obtained from their cousins with normal vinculin genes.

    To gauge whether these cell changes led to difference in cardiac function, the investigators performed something akin to a human heart stress test. They immersed the insects' isolated beating hearts into a thick solution, forcing them to work harder than they normally would. The hearts of flies with normal vinculin tolerated exertion much better than the hearts of vinculin-deficient flies. So did the hearts of the once vinculin-deficient flies that the researchers had genetically altered to produce more of the protein.

    In a final step, the investigators studied the interior of heart cells. Cells encircled by vinculin had a markedly well-organized interior, their contraction-fueling muscle proteins in a near-perfect arrangement. By contrast, muscle proteins inside heart cells from vinculin-deficient flies had a decidedly more disordered pattern of arrangement.

    "What we saw was an exquisite visual proof of the principle that form dictates function," Dr. Cammarato said. "Encircling the cell like a rubber band, vinculin appears to keep its interior impeccably arranged and in doing so ensures that form and performance remain intact."

    "Vinculin appears to be at the heart of a natural defense mechanism that reinforces the aging heart cell and helps it better sense and respond to age-related changes," noted Dr. Engler, the study’s senior author. “The results of this study implicate vinculin as a future candidate for therapy for people at risk of age-related heart failure.”

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