AsianScientist (Oct. 3, 2014) – More commonly known as the “Asian flush” gene, scientists have now used induced pluripotent stem (iPS) cells to study how mutations in aldehyde dehydrogenase 2 (ALDH2) impact a person’s risk of heart disease. This research has been published in Science Translational Medicine.
Over 500 million people worldwide carry a genetic mutation that disables a common metabolic protein called ALDH2. The mutation, which predominantly occurs in people of East Asian descent, leads to an increased risk of heart disease and poorer outcomes after a heart attack. However, the role of ALDH2 in heart disease has not been well studied, due to the difficulty of obtaining and maintaining human heart samples.
To circumvent this problem, researchers at the Stanford University School of Medicine turned to iPS cells, comparing heart muscle cells made from iPS derived from donors with and without ALDH2 mutations.
“People have studied the enzyme ALDH2 for many years in animal models,” said Dr. Antje Ebert, lead author of the study. “But there are many significant differences between mice and humans. Now we can study actual human heart muscle cells, conveniently grown in the lab.”
Starting with skin samples donated by ten men of East Asian descent aged between 21 and 22 years, the researchers created iPS cells before coaxing them into developing to heart cells. They then compared how the newly created heart cells responded to low-oxygen conditions.
They found that cells with the ALDH2 mutation produced higher levels of reactive oxygen species and were more likely to undergo programmed cell death than cells without the mutation. Further study identified the involvement of a protein called JNK that is involved in cell signaling known to stimulate programmed cell death.
“This is an entirely new function attributed to this well-known metabolic enzyme,” said Dr. Ebert. “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.”
The researchers plan to further investigate the signaling mechanisms and structural DNA changes that may occur in the presence of the mutation in the ALDH2 gene. This will also allow research on drugs that would increase the activity of the ALDH2 protein in carriers with one good copy and one mutated copy of the gene, which might become a useful therapy for coronary artery disease and heart attacks.
“This study is one of the first to show that we can use iPS cells to study ethnic-specific differences among populations,” said Dr. Joseph Wu, director of the Stanford Cardiovascular Institute and professor of cardiovascular medicine and of radiology.
“In the future, I believe we will have banks of iPS cells generated from many different ethnic groups. We’d like to include male and female patients of major representative ethnicities, age ranges and cardiovascular histories. This will allow us to conduct ‘clinical trials in a dish’ on these cells, a very powerful new approach, to learn which therapies work best for each group.”
The article can be found at: Ebert et al. (2014) Characterization of the Molecular Mechanisms Underlying Increased Ischemic Damage in the Aldehyde Dehydrogenase 2 Genetic Polymorphism Using a Human Induced Pluripotent Stem Cell Model System.
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Source: Stanford School of Medicine.
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