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At the Bench: Unraveling Pulmonary Hypertension

Working with cells that line the innermost layer of the blood vessels, Johns Hopkins investigators say they have made a leap forward in understanding the underlying biology behind pulmonary hypertension, a dangerous type of high blood pressure in lungs that ultimately leads to right heart failure and death.

By conducting experiments in endothelial cells, they discovered that a protein called KLF15 (Kruppel-like factor 15) protects these cells from damage in the event of severe conditions, such as oxygen deprivation, that may lead to pulmonary hypertension. They went on to show that KLF15 is likely a key regulator of genes important for maintaining proper function of lung blood vessels. Interestingly, it may protect the cardiovascular system from conditions that are similar to what animals experience during hibernation.

During a state of reduced oxygen, levels of KLF15 can drop, causing a series of chain reactions that likely contribute to blood vessel damage and the progression of pulmonary hypertension.

In proof-of-concept studies, the investigators were able to genetically alter cells grown in a dish in a way that caused them to have increased expression of KLF15 and reverse the damage—restoring the cells to normal function despite exposure to low oxygen levels. A description of the experiments and outcomes, published online in Arteriosclerosis, Thrombosis, and Vascular Biology, suggests new targets for drug development for pulmonary hypertension.

“Our experiments advance our understanding of the way low oxygen levels make blood vessels sick,” says Lewis Romer, professor of anesthesiology and critical care medicine and senior co-author of the study. “The findings also potentially advance the search for drugs that not only control pulmonary hypertension but also may reverse the disease or cure it.”

In the United States, pulmonary hypertension is considered a rare disease, affecting about 109 per 1 million people under age 65 and 451 per 1 million over age 65, Romer says. The condition may be managed through medications that maximize blood flow through the lungs or, in severe cases, a heart or heart-lung transplant. Pulmonary hypertension accounts for an estimated $4.9 billion to $5.8 billion in annual health care spending worldwide, Romer says. Left untreated, half of people with the condition may die within two to five years of diagnosis, he says, “so it’s very important for the medical community to get a better handle on what’s going on with the underlying disease.”