October 26, 2020 | It has been known for several years now that a “danger molecule” shows up in the blood when cells in the body are under stress or tissues are injured, inducing a potent inflammatory response—at least in rats. High Mobility Group Box-1 (HMGB1) is in fact one of the best characterized damage-associated molecular patterns (DAMPs), and heightened serum levels of the protein in rodents have been associated with obesity and appear to play a role in the pathogenesis of cardiovascular disease, according to Yanbin Dong, M.D., Ph.D., faculty member in the Medical College of Georgia’s department of medicine and its Georgia Prevention Institute.
But until now, no counterpart studies have been done in humans. A research team comprised of scientists from the Medical College of Georgia at Augusta University, Duke University Medical Center, Medical University of South Carolina, and the University of Massachusetts Medical School recently published the first longitudinal study to comprehensively examine the associations of human HMGB1 with several inflammatory markers, obesity, and subclinical cardiovascular disease risk.
Findings appeared in Arteriosclerosis, Thrombosis and Vascular Biology (DOI: 10.1161/ATVBAHA.120.314599) and confirmed a hunch that higher circulating concentrations of HMGB1 correlated with the development of chronic low-grade inflammation, obesity, and subclinical cardiovascular risk, Dong says. It also demonstrated age, sex, and race differences in HMGB1 levels that are only partially understood.
Following 489 participants over eight and a half years revealed that the amount of HMGB1 in the blood rises with age and is generally higher in blacks than whites and in females than males, continues Dong, a molecular geneticist and cardiologist who has been studying the underpinnings of obesity, diabetes, and hypertension for the past 25 years. The study involved four follow-up visits and the collection of 1,149 blood samples.
Study participants are part of the longitudinal Georgia Stress and Heart Study seeking to learn more about the development of cardiovascular risks and enrolled as healthy 5- to 16-year-olds, he says. They had an average age of about 25 when they had their first blood samples drawn at the Georgia Prevention Institute.
Smaller clinical studies have been done showing levels of the danger molecule are higher in individuals with a high waist-hip ratio compared to people with less fat around the middle, he says. HMGB1 has also been associated with higher blood pressure, higher levels of interleukin 6 (IL-6, a small cytokine secreted by immune cells in response to injury or infection) and having heart disease.
Subgroup Analysis
HMGB1 is needed inside cells to help manage the architecture of chromosomes, says Dong. But, like all DAMPs, HMGB1 becomes a problem when it gets secreted into the extracellular space and initiates an “inflammation cascade.” Some sort of injury or stress (including mental stress) triggers its release—and the list includes the lung damage and resulting cytokine storm seen in severe cases of COVID-19.
It's somewhat unsurprising that obese individuals have higher blood levels of HMGB1 because they have more fat cells that secrete the protein, says Dong. Ditto the elderly since more cell death occurs with aging.
More perplexing are the heightened levels seen in blacks and females. Blacks tend to have more severe cardiovascular and cerebrovascular problems starting at a younger age than whites, so an early, heightened inflammatory response is likely a factor, says Dong. Females generally have a higher proportion of HMGB1-secreting adipose tissue than males, he adds, although younger women might be getting some unique cardiovascular protection from estrogen prior to menopause.
Across the board, he notes, increases in HMGB1 were accompanied by increases in proinflammatory factors like C-reactive protein, IL-6 and tumor necrosis factor as well as stiffer arteries and generally higher blood pressure. A lot of “bad synergy” exists between those factors—IL-6 prompts the liver to make C-reactive protein, for example, and higher C-reactive protein was consistently associated with increasing age, being female, and obesity.
Further studies are required before HMGB1 gets deployed as a biomarker of health or disease in clinical settings, Dong says. HMGB1 levels need to be compared in hypertensive versus non-hypertensive patients, for instance. Since obesity sets the stage for diabetes, researchers might also want to explore if an elevated level of HMGB1 is a risk factor for the disease. Normative values in the general population are also unknown.
Future planned work includes pursuing HMGB1 as a potential biomarker for blood vessel disease such as heart attack and stroke, as well as a potential prognostic indicator for how these diseases will progress and how patients are responding to treatment, says Dong. Researchers will be also conducting randomized clinical trials to study if HMGB1 could be lowered by lifestyle modifications such as healthy eating and regular excise and pharmacological treatment.