You’ve probably never thought about it this way, but whether or not you develop a disease like heart disease, cancer, stroke or chronic obstructive pulmonary disease (COPD) depends, in large part, on how the cells of your body respond to oxygen. Because these diseases cause about two-thirds of all the deaths in the US, understanding these cell reactions is a big deal…in fact, it’s big enough to win a Nobel Prize.
How the journey began: The story of this groundbreaking discovery began in 1995 when researchers at Johns Hopkins University, led by Gregg L. Semenza, MD, PhD, identified a protein that controls how cells respond to low levels of oxygen (hypoxia). Twenty-four years later, Dr. Semenza was awarded the 2019 Nobel Prize in Physiology or Medicine for his seminal work on this protein, which was dubbed hypoxia inducible factor-1 (HIF-1).
What is HIF-1? Simply put, it is a type of protein that binds to part of your DNA, allowing it to turn on or off genes that control cell functions. As such, HIF-1 is the so-called “master regulator” for genes that regulate your cellular response to oxygen. This is important because the low levels of oxygen that occur with hypoxia can be deadly to cells.
Think of it this way: The human body has about 100 trillion cells that need a steady supply of oxygen. Imagine if, say, FedEx had to make 100 trillion deliveries 24 hours a day…every day. At the cellular level, that is the scope of the body’s oxygen supply challenge.
To protect cells, HIF-1 turns on genes that increase oxygen in several ways. For example, HIF-1 can increase the production of red blood cells, which carry oxygen to cells, by triggering production of a hormone called erythropoietin (EPO). EPO is made in your kidneys, but it triggers production of red blood cells in your bone marrow.
HIF-1 also can increase oxygen by promoting the growth of new blood vessels to deliver oxygen to the body’s tissues—a process known as angiogenesis. This occurs when HIF-1 activates a protein called vascular endothelial growth factor (VEGF).
In the presence of hypoxia, HIF-1 triggers glycolysis, a process that breaks down glucose to promote the production of cellular energy.
When it comes to the effects of HIF-1, there’s good news and bad news. By increasing oxygen-carrying red blood cells…creating new blood vessels…and activating glycolysis, HIF-1 can help prevent the cell damage that results from diseases caused by decreased blood supply, such as anemia, heart attack, stroke and diabetes.
On the other hand, HIF-1 can worsen such diseases as cancer, COPD and certain eye diseases of the retina. Here’s how that happens with…
• Cancer. With a developing malignancy, cells divide very rapidly, which uses up lots of oxygen and causes hypoxia. HIF-1 can be activated by hypoxia in cancer cells to provide more oxygen and increase their blood supply. In cancers that grow quickly and spread (metastasize), HIF-1 is more active (overexpressed), research shows.
• COPD. With COPD, HIF-1 is required for the constriction of pulmonary blood vessels in response to hypoxia. This constriction makes it more difficult for the heart to pump blood to the lungs, which can lead to heart failure.
• Eye disease. Blood flow into and out of the retina (the thin layer of sensory tissue that lines the back of the eye) can be impaired due to a condition such as diabetes. To compensate for the lack of oxygen, HIF-1 kicks into high gear, triggering new blood vessel growth, which gradually covers the retina, leading to ischemic retinopathy, a major cause of blindness among people with diabetes.
Depending on the disease, either increasing or blocking HIF-1 activity could be beneficial. Treatments that increase HIF-1 activity are called HIF-1 inducers, while those that block HIF-1 are called HIF-1 inhibitors. With studies now under way in animals and humans, such treatments are close to becoming a reality.
For example, an HIF-1 inducer is being studied to treat anemia due to chronic kidney disease, which causes your kidneys to stop making the hormone EPO. The reduced EPO production inhibits the production of red blood cells, leading to anemia. To treat this anemia, researchers have developed a man-made (recombinant) form of EPO. However, the major drawback of recombinant EPO is that it must be injected, whereas HIF-inducers are administered as pills that can be taken by mouth.
Final-stage human studies show that an oral HIF-1 inducer medication, called a small-molecule drug, is a more natural and effective way to increase EPO and reverse anemia. One of the HIF-inducers (roxadustat) has been approved for use in China and Japan. There are large clinical trials under way in the US, the results of which will determine whether the medication gets FDA approval. The decision will probably be made in the next year or two.
Meanwhile, an HIF-2 (a closely related protein) inhibitor drug is in clinical trials for the treatment of kidney cancer. So far, the drug has only been tested in a phase 1 trial, which tests drug safety, not drug efficacy. However, the results are promising.
In the next 10 years, several FDA-approved treatments should become available for diseases using HIF-1 inducers and inhibitors. In addition to those discussed earlier, treatments for conditions including heart attack, stroke, COPD, wounds, diabetes and even spinal cord injury are hoped for in the future.
Latest development: HIF-1 gene therapy—by promoting blood vessel growth in the legs, for example— might be useful for the treatment of localized disease, such as limb ischemia, a narrowing or blockage of an artery that significantly reduces blood flow.
