Researchers from the Stanford University School of Medicine have recently utilized healthy, but unusable, donor heart tissue to study the genetic components involved in heart failure. This has allowed these scientists and their collaborators to map out genetic activity and connectivity that occurs when the heart shuts down and identify a gene that is potentially at the center of this process. This work was covered today in Nature Communications.
“Let’s say we traced the whereabouts of the human resources department at Stanford,” said Euan Ashley, MB ChB, DPhil, professor of medicine, of genetics and of biomedical data science at Stanford. “These networks are akin to social networks. We could see that they tend to park in the same area, go to the same office, and get lunch in the same place. They move together, and so it can be reasonably inferred that they are somehow related to each other.”
This is similar to tracing the gene network for heart failure, with physical movements being replaced by changes in gene expression. These changes were closely monitored by Ashley and his team to observe what happens as the heart begins to fail.
The team has identified one specific gene, PPP1R3A, that appears to play a central role in this process, being that its genetic activity is very similar to that of its surrounding genes. Ashley also noted that disabling this gene in animal (mouse) models of cardiac disease, the subjects were protected from heart failure. Using mouse models of hypertension, the researchers found that the mice lacking PPP1R3A maintained normal cardiac function, whereas those with the gene experienced heart failure.
“This study has a truly unique angle, which is that we had precious, healthy human tissue and we used it to tell us something new about how a disease manifests,” explained Victoria Parikh, MD, clinical instructor of cardiovascular medicine. “And now someday we might even be able to translate that into a treatment.”
Ashley explained that heart failure describes the heart’s inability to pump blood and that this can be caused by several conditions, including heart attack, hypertension, valve misfunction, or genetic causes. He noted that regardless of what the cause is, this research suggests that there is a single pathway that leads to heart failure. This network of genetic factors that the researchers have mapped out gives insight as to how this central pathway is activated.
Most previous research analyzing the genomics of healthy hearts and failed hearts has taken place in mouse models; however, Ashley and colleagues have used human donor tissue to analyze human genetics. Though fewer pathways are were found to be involved in heart failure than healthy heart function, the team noted that there were more genes involved in these detrimental pathways. Ashley claimed that PP1R3A’s role at the center of this regulation makes sense because it plays a role in metabolizing glucose, the energy source that cardiac cells switch to during failure.
“Maybe someday we’ll be able to peer into a cell and watch as the networks are actively changing in real time,” he said. “But right now, what we have is human tissue that’s sort of frozen at a moment in time, and so we can use that to look at which genes are involved in this process.”
Ashley was the senior author of the paper regarding the team’s findings. Parikh is a lead author of the study as well, alongside Pablo Cordero, PhD, former Stanford graduate student.
Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure, from @vnparikh @tsuname @euanashleyhttps://t.co/dxnwQhyrhZ
— NatureCommunications (@NatureComms) June 24, 2019
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