Running low on oxygen is a major danger for body tissues, but the heart is particularly sensitive to such hypoxic conditions, which can lead to long-term tissue damage or even heart attacks.
In new studies conducted at UC San Francisco, a novel oxygen-delivery therapeutic restored the function of oxygen-starved heart tissue in an animal model of global hypoxia. The findings appeared in the Journal of PLOS Biology.
Unlike its experimental predecessors, the new drug, called OMX-CV, does not appear to cause systemic side effects or overcorrect with excessive blood oxygenation, which can itself be toxic. Instead, the new drug delivered its precious oxygen cargo only to the tissues that need it most.
"Any tissue with compromised blood flow, whether due to trauma, stroke, or heart disease, could potentially be targeted by a treatment like this," said Emin Maltepe, co-senior author of the paper.
Cardiovascular diseases such as coronary artery disease can starve the heart of oxygen, triggering cardiac dysfunction or heart attacks in adults, but hypoxia in the heart is also a problem in children. According to the Centers for Disease Control and Prevention (CDC), about 10,000 children are born each year with a critical congenital heart defect. Many of these infants require heart surgery within their first year of life, during which blood may be temporarily removed from the heart, leaving the organ starved for oxygen.
Under normal conditions, the heart consumes more oxygen by weight than any other organ, and when oxygen levels are low; its demand soars even higher. The hypoxic heart pumps harder to deliver oxygen to the rest of the body, and paradoxically, requires more and more oxygen itself to maintain function. An oxygen-delivering drug like OMX-CV could ease the physical stress of hypoxia and improve recovery following heart attacks or after open heart surgery in adults and children.
Also, hemoglobin-based drugs have proven too good at their jobs: they tend to flood the blood with excess oxygen that can itself cause serious tissue damage. Moreover, when outside the bounds of a red blood cell, hemoglobin can grab hold of nitric oxide, a natural muscle relaxant found in blood vessels. Vessels robbed of nitric oxide constrict, causing blood pressure to jump, raising the risk of heart attack and decreasing blood flow to important organs like the kidneys.
OMX-CV sidesteps these problems by employing an engineered bacterial protein known as H-NOX as its base, rather than hemoglobin. H-NOX proteins contain a "co-factor" called a heme group -- the same co-factor that gives hemoglobin its name -- which allows the protein to bind not only oxygen but also nitric oxide. By modifying the chemical structure of H-NOX proteins, Omniox scientists re-engineered them to hold tight to oxygen, but leave nitric oxide alone.
The researchers also showed that the modified proteins bind oxygen so tightly that they only relinquish their grip when they come across a severely hypoxic tissue.
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