Asians' Heart Health Affected By Genetic Mutation; Scientists Use Specialized Stem Cells To Study ALDH2 Protein

Pluripotent stem cells
To study the effect of mutations on heart health, scientists compared heart muscle cells made from iPS cells, from people with the mutation versus those without the mutation. Photo courtesy of Shutterstock

Researchers studying the causes of heart diseases in Asian populations had so far focused on their diets. But a new study reveals that a genetic mutation that disables a common metabolic protein called ALDH2, predominantly found in people of East Asian descent, leads to an increased risk of heart disease and poorer prognosis after a heart attack. The mutation also causes facial flushing, referred to as the "Asian Glow," when carriers drink alcohol.

Studies on this mutation, carried by around eight percent of the world’s population, will help clinicians develop therapeutics for heart diseases caused by it. The findings of the study, conducted by Stanford University School of Medicine researchers, have been published in the journal Science Translational Medicine.

Researchers used pluripotent stem cells (iPS) from carriers and non-carriers of the mutation to understand how it affects heart health. Pluripotent cells are also called "true" stem cells, as they can be grown into any type of specialized cell. The iPS cells in this study were created from skin samples donated by 10 men, ages 21 to 22, of East Asian descent. Of the 10, five men carried the ALDH2 mutation and the others did not.

Mutations in ALDH2

Aldehyde dehydrogenase 2 is the protein encoded by the ALDH2 gene. It is involved in several metabolic processes and plays a role in cell survival. Specifically, it plays an important role in programmed cell death, called apoptosis, in response to stressful growing conditions. It does so by neutralizing toxic aldehydes, formed by a class of compounds called reactive oxygen species.

In people carrying the mutation in one of the two copies of the ALDH2 gene, the gene is unable to produce sufficient amounts of the protein to destroy the reactive oxygen species, which accumulates and causes programmed cell death in situations of stress, such as heart attacks.

In the skin samples they obtained, the researchers found that skin cells with the mutation in the ALDH2 gene had strongly decreased function of the ALDH2 protein compared with the cells without the mutation. The mutated cells also had significantly higher amounts of reactive oxygen species, and grew more slowly than the other cells.

They then used the skin iPS cells to create specialized heart cells called cardiomyocytes and subjected them to low-oxygen conditions. Cardiomyocytes with the ALDH2 mutation had higher levels of reactive oxygen species in response to low oxygen levels than those without the mutation, but this difference could be alleviated by treating the cells with a compound that boosts activity of the ALDH2 protein in patients with one unmutated copy of the gene.         

Mutated cells also had less viability and were more prone to undergo programmed cell death than cells without mutation.

"It's the first time ALDH2 has been shown to play a role in cell survival. Now we have come to understand that when the ALDH2 gene is mutated, cells are more likely to undergo programmed cell death, causing tissue damage,” said author Antje Ebert in a statement.

The researchers plan to conduct many more investigations to fully understand the role of ALDH2 in maintaining heart health. They also plan to start a biobank of iPS cells from about 1,000 people of many different ethnic backgrounds and health histories. This, they say, will allow them to conduct clinical trials on these cells in the lab and help them develop therapies that suit different populations.

Source: Kodo K, Liang P, Wu H, et al. Science Translational Medicine. 2014.

 

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