Levels of HO-1 enzyme elevated in SCD patients, especially children
New findings highlight enzyme's 'potential protective role' against toxicity
Blood levels of heme oxygenase-1, or HO-1, an enzyme that helps protect cells from certain types of damage, are elevated in people with sickle cell disease (SCD), especially children, a new study showed.
HO-1 serves as a safeguard against the toxic effects of free heme, a molecule present in red blood cells. It’s elevated in the blood of people with SCD due to the excessive red blood cell destruction that marks the genetic disease.
“These findings highlight the pronounced elevation of HO-1 in pediatric SCD patients, suggesting its potential protective role against heme-induced toxicity, especially during childhood,” the researchers wrote.
The team will now seek to better understand the role of this enzyme and to explore therapeutic approaches to increase HO-1 levels — indicating activity — which is expected to reduce SCD-related complications.
The study, “Elevated serum heme oxygenase-1 in pediatric sickle cell disease: Insights from the SickleGenAfrica Network,” was published in the journal HemaSphere.
Due to genetic mutations, people with SCD carry a faulty version of hemoglobin, the protein in red blood cells that helps carry oxygen through the body. Consequently, red blood cells are misshapen and rigid, allowing them to block blood vessels and compromise blood flow.
These abnormal red blood cells are also broken down more quickly than normal. When red blood cells are destroyed — a process called hemolysis — their components are released into circulation. One such component is heme, a component of hemoglobin.
Excessive hemolysis in SCD leads to toxic levels of free heme in circulation, causing inflammation and cellular damage. This process contributes to SCD complications, including pain episodes known as vaso-occlusive crises and a life-threatening type of lung injury called acute chest syndrome.
SCD patients had 20 times higher HO-1 than healthy people
HO-1 is an enzyme that breaks down free heme into harmless byproducts, helping to buffer against toxicity when heme levels are too high. The body naturally makes more of the enzyme when free heme levels rise.
Animal studies have indicated that the enzyme has a protective effect in SCD mouse models, with potentially greater benefits at a younger age, according to the researchers.
Now, an international team of scientists from Yale School of Medicine in the U.S. and its partner institutions in Ghana in West Africa analyzed blood HO-1 levels from 2,309 children and adults with SCD.
These SCD patients are enrolled in the SicklGenAfrica Network, a large research effort designed to investigate how genetic factors influence SCD. The median age of the patients was 12, with 60% younger than 16.
Anna Sowa, MD, the study’s first author and a PhD candidate at the investigative medicine program at Yale, noted that this is the first large study of HO-1 in SCD.
In a university press release, Sowa noted that the results showed that the average circulating HO-1 levels in the SCD patients were about 20 times higher than levels reported in healthy people.
Enzyme levels in blood peak in childhood, dropping by early adulthood
Blood HO-1 levels were found to be age-dependent, peaking during childhood — at about 6-10 years of age — and dropping sharply between adolescence and early adulthood, according to the researchers. Children younger than 16 had median HO-1 levels nearly three times higher than those of individuals ages 16 and older, the team noted.
The age-related pattern was consistent across sex and genetic SCD subtypes. It also held regardless of patients’ use of hydroxyurea, an oral medication designed to reduce the frequency of pain crises in people with sickle cell anemia, the most common and often the most severe form of SCD.
Significantly higher levels of the enzyme were observed in males versus females. Individuals with the Hb SS genetic profile — generally linked to more severe disease — also had significantly higher enzyme levels relative to people with the usually milder Hb SC profile.
Consistent with previous studies, hemoglobin levels were lower than normal in all SCD patients, as were the levels of two scavenging proteins that help transport heme to the liver for degradation. The researchers also noted that children younger than 16 showed significantly lower levels of these scavenging proteins compared with adults.
“Our study demonstrates a significant elevation of HO-1 levels in individuals with SCD, with an especially robust HO-1 response in children,” the researchers wrote.
Understanding the mechanisms underlying HO-1 regulation in SCD may open avenues for novel therapeutic strategies aimed at augmenting HO-1 [levels] or activity, or delivering synthetic HO-1, to mitigate disease complications.
The observed increase in blood HO-1 levels of SCD patients could be a protective response to prevent toxicity, especially given that other scavenging proteins, which normally help, are depleted, the team noted.
The even higher levels of the enzyme in children could partly be because hemolysis is more pronounced in younger SCD patients, according to the team.
“Understanding the mechanisms underlying HO-1 regulation in SCD may open avenues for novel therapeutic strategies aimed at augmenting HO-1 [levels] or activity, or delivering synthetic HO-1, to mitigate disease complications,” the researchers concluded.
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