Cornell researchers improved heart function and extended survival in mice used to model an inherited form of heart disease by reducing damage to the nuclei of heart muscle cells.
The study in Circulation Research points to a possible way to interrupt the inflammation and scarring associated with LMNA-related dilated cardiomyopathy. The experiment tested a genetic intervention in mice, rather than a treatment in patients.
The work was directed by Jan Lammerding, a professor in Cornell's Meinig School of Biomedical Engineering and a member of the Weill Institute for Cell and Molecular Biology. Noam Zuela-Sopilniak and Julien Morival jointly led the research; Cornell professor Iwijn De Vlaminck was a co-corresponding author.
Mutations in the LMNA gene affect lamin A and lamin C, proteins that help give a cell's nucleus structural support. LMNA-related cardiomyopathy can lead to heart failure and sudden cardiac death.
Reducing strain on fragile nuclei
The researchers used adult mice engineered so lamin A/C could be depleted specifically in heart muscle cells. They studied heart tissue early and later in disease, comparing gene activity, cell types and their locations in affected and control hearts.
Nuclear ruptures were concentrated in a subset of heart muscle cells and were associated with inflammatory signaling, immune-cell activity and scarring. The findings supported a model in which damage to the nucleus helps drive harmful communication between muscle cells, immune cells and cells that produce scar tissue.
The team induced expression of an engineered protein called DN KASH at the same time it induced lamin depletion in the adult mice. DN KASH disrupts the LINC complex, which transmits mechanical forces from the rest of a cell to its nucleus. This tested the effects of reducing nuclear strain as the disease model developed.
DN KASH reduced nuclear rupture in the affected heart muscle cells. In the paper's survival comparison, 23 mice with the combined intervention were followed alongside 20 mice with lamin depletion alone, as well as control groups.
Mice with lamin depletion alone had a median survival of less than five weeks. The combined intervention extended survival from weeks to months, with some mice still alive at the 400-day endpoint. Deaths occurred in both the male and female intervention groups, with females surviving longer overall. Heart function improved substantially, although it was not completely restored.
Gene activity and the limits of the model
The intervention normalized the activity of more than half the genes whose activity had changed with lamin depletion, even though lamin A/C remained depleted. The researchers said this supports the idea that many harmful changes occur downstream of nuclear damage.
An analysis of existing human heart data found related gene-expression patterns. Those human samples represented end-stage disease, while the mouse work allowed researchers to study earlier changes.
The authors identified differences that matter for interpreting the results: human LMNA disease arises from inherited mutations that can affect development and other cell types, while their model abruptly reduced lamin proteins in adult heart muscle cells. They also noted that changes in gene activity do not always predict changes in protein levels or function, and further work is needed to test the proposed mechanisms.
In a Cornell account of the work, Lammerding said the team is interested in exploring whether nuclear damage also contributes to other heart conditions, including injury after a heart attack and aging.
The research was supported by the National Institutes of Health, National Science Foundation, American Heart Association, Leducq Foundation, Cornell programs and gifts from the family of Ray and Kathy Mills. The authors reported no conflicts of interest.
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