It's fairly easy to give mice hypertension. Just regularly dose them with the hormone angiotensin II. But mixing a molecule called 2-HOBA into the animals' drinking water returns their blood pressure almost to normal, vascular biologist David Harrison of the Vanderbilt University School of Medicine in Nashville and colleagues have found. Now, that observation could open an innovative approach to treating hypertension in people.
Derived from buckwheat, 2-HOBA stands out because of the way it seems to work—by influencing immune cells. "The immune system is an unexpected but important player in hypertension," says vascular biologist Tomasz Guzik of the University of Glasgow in the United Kingdom. Scientists now suspect that immune cells collude with long-recognized culprits such as stress and dietary salt to drive up blood pressure. Safety tests of 2-HOBA in people are already underway, and Harrison, who holds a patent on its use for hypertension, hopes to launch a full clinical trial, which might lead to a new class of treatments that work by restraining the immune system.
More than 1 billion people worldwide have high blood pressure, which promotes heart attacks, strokes, kidney damage, dementia, and other ailments. Current drugs include diuretics that reduce the amount of water in the body and β blockers that decrease how much blood the heart pumps. Yet about 15% to 20% of patients don't improve. "Clearly, we are not managing the condition appropriately at the moment," says vascular biologist Grant Drummond of La Trobe University in Melbourne, Australia.
Scientists first suggested that the immune system modifies blood pressure more than 50 years ago. But a 2007 study by Harrison, Guzik, and colleagues was a watershed. The researchers infused angiotensin II into mice genetically altered to lack two types of immune cells: B cells and T cells. The animals' blood pressure remained about 20 points below that of controls, which also received the hormone. When the researchers restored T cells to the modified rodents, however, their blood pressure surged. That result "was a major finding that triggered the explosion of interest in the field," says nephrologist Thomas Coffman of the Duke-National University of Singapore Medical School.
In 2011, cardiovascular biologist Ernesto Schiffrin of McGill University in Montreal, Canada, and colleagues took the opposite tack. They infused immune-suppressing regulatory T cells into hypertensive mice and reported that the cells reined in blood pressure and reduced the amount of blood vessel damage the animals suffered. "The data, at least in animal models, are compelling that the immune system is involved in hypertension," Coffman says. Some human studies also indicate a connection. In a 2006 paper, for example, researchers revealed that blood pressure declined by more than 10% after patients with psoriasis or rheumatoid arthritis began taking an immune-inhibiting drug.
Researchers doubt that immune cells instigate hypertension. "The immune system probably kicks in after some of the more traditional risk factors are present," Drummond says. These factors, which can include a high-salt diet, stress, and a naturally overactive sympathetic branch of the nervous system, spur an initial increase in blood pressure that damages blood vessels. Immune cells detect that damage, and their response sparks "a vicious circle that leads to the progressive elevation of blood pressure," Schiffrin says.
Among other effects, immune cells disrupt the function of the endothelial layer, the lining of the blood vessels, counteracting "all the good things that the endothelial cells produce," says physiologist Brett Mitchell of Texas A&M College of Medicine in College Station. For example, those cells normally emit nitric oxide, which relaxes blood vessels and reduces blood pressure—and immune cells inhibit nitric oxide production. The cells also wreak havoc in the kidneys, stimulating the organs to hold on to more sodium, which in turn spurs the body to retain more water.
"The question of the decade," Harrison says, has been what switches on the immune cells. His team thinks it has isolated one signal: oxidized lipids known as isoketals that form inside blood cells. In 2014, he and his colleagues discovered that these molecules are unusually abundant in certain immune cells of mice with high blood pressure—and that the same is true in patients with hypertension. Isoketals adhere to and damage proteins, and Harrison's group found that the resulting injured proteins stimulate immune cells known as dendritic cells, which in turn activate T cells. It's "a pretty good case," says nephrologist Richard Johnson of the University of Colorado Anschutz Medical Campus in Aurora.
Harrison's potential blood pressure treatment, 2-HOBA, thwarts isoketals by muzzling their reactive ends. That probably won't impair our defenses against pathogens. But researchers are divided over whether to test the more powerful immune-suppressing drugs that patients take for illnesses such as psoriasis, Crohn disease, and rheumatoid arthritis. Schiffrin argues that these drugs are too risky to use in hypertension, which people can live with for decades. "We don't want to produce fatal symptoms in a patient … because we were playing around with their immune system."
Drummond, however, says such drugs could serve as short-term treatments for people who don't respond to other therapies. "It is so important that we get blood pressure under control," he says, that "there is strong justification" for a clinical trial to test some of these drugs.