Natural antioxidant bilirubin may improve cardiovascular health

Bilirubin, a yellow-orange pigment, is formed after the breakdown of red blood cells and is eliminated by the liver. It's not only a sign of a bruise, it may provide cardiovascular benefits, according to a large-scale epidemiology study.

A recent analysis of health data from almost 100,000 veterans, both with and without HIV infection, found that within normal ranges, higher levels of bilirubin in the blood were associated with lower rates of heart failure, heart attack and stroke.

The results are published in the Journal of the American Heart Association.

Several studies have suggested that bilirubin may have beneficial effects, by acting as an antioxidant or interfering with atherosclerosis. The data from the veterans adds to this evidence, and specifically looks at people living with HIV and at an anti-HIV drug, atazanavir, known to elevate bilirubin. The researchers did not see an independent effect of atazanavir on cardiovascular risk.

Even if well-controlled by antiretroviral drugs, HIV infection has negative effects on cardiovascular health, says lead author Vincent Marconi, MD.

"We initially wanted to see if bilirubin and cardiovascular disease had a different relationship in people who were HIV positive, compared to HIV negative," says Marconi, professor of medicine and global health at Emory University School of Medicine and Rollins School of Public Health. He is also director of infectious disease research at the Atlanta Veterans Affairs Medical Center.

Study authors include VACS principal investigator Amy Justice, MD, Ph.D. from Yale, Matt Freiberg, MD and others from Vanderbilt, Jeff Lennox, MD from Emory and additional investigators from Vanderbilt, Boston University, Penn, Pitt, UCLA and Baylor.

Marconi and his colleagues examined data from the Veterans Aging Cohort Study, a nationwide look at HIV infection, supported by the National Institutes of Health. VACS data included 31,418 HIV-positive and 66,987 HIV-negative veterans, almost all men and 48 percent African American. Their age was an average of 48 years.

The researchers divided study participants into four groups according to their bilirubin levels.

Higher levels of bilirubin meant lower risk of heart attack, heart failure or stroke. The group with the highest level of bilirubin had 76 percent of the risk for combined cardiovascular events as the group with the lowest level, with effects seen even in people without liver disease.

"Large increases in bilirubin were not required to see an effect on CVD risk reduction," Marconi says. "Most of the change happened well within the normal physiologic range and specifically from the first to the second quartile."

Atazanavir is a HIV protease inhibitor, and is designed to stop HIV from processing itself. It has a side effect on an enzyme in human cells that is necessary for the recycling of bilirubin. There are some indications that the drug itself has negative effects, balancing out the benefits of bilirubin, Marconi adds.

The authors conclude:

This work provides epidemiologic rationale for future studies to investigate how the antioxidant effect of bilirubin could be harnessed to reduce chronic disease morbidity risk. Future studies should explore the use of bilirubin as a biomarker for other inflammation‐mediated conditions and all‐cause mortality...

More at : http://jaha.ahajournals.org/content/7/10/e007792

Antioxidant compound could be effective to combat immune rejection after islet transplantation

A team of researchers has found that doses of bilirubin help provide suppression of the immune response following islet transplantation in mouse models. Bilirubin also significantly decreased islet cell death after the cells had been isolated and undergone nutrient deprivation and hypoxic (low oxygen) stress. If applied, the results of the study are expected to improve outcomes after allograft (other donated) islet cell transplantation to treat type 1 diabetes.

Carried out by researchers at North Carolina State University, Ohio State University and the University of California Irvine, the study will be published in a future issue of Cell Transplantation  

"Pancreatic islet transplantation has the potential to provide a potentially curative, non-invasive treatment for type 1 diabetes," said Dr. Christopher A. Adin, associate professor, College of Veterinary Medicine, North Carolina State University. "However, stress and injury can cause up to a 70 percent loss of cells in the first 72 hours after transplantation. We hypothesized that bilirubin, an antioxidant, could be used as a supplement to suppress the immune response to allograft islet transplantation. In this study with mice, we administered bilirubin to the pancreas before procurement or added it to a culture after islet isolation."

Bilirubin, a cytoprotectant, has been shown to improve outcomes in cases of sepsis and in solid organ transplantation, said the researchers. The current study, however, is the first to investigate bilirubin as an islet allograft protectant from the immune response and other cell death-causing injury.

The researchers found that bilirubin supplementation could suppress the damage caused by the release of "damage-associated molecular patterns" (DAMPs) that included types of foreign cell-fighting immune cells.

Their studies also revealed that bilirubin also has a direct effect on the phenotype - the physical appearance - of the antigen cells that fight against engraftment, especially macrophages, a type of cell that engulfs and digests cellular debris and foreign substances.

Taken together, that bilirubin can suppress DAMP release, alter cytokine profiles, and affect macrophages, suggests that the use of this natural antioxidant may provide a method for pre-conditioning to improve outcomes after islet allograft transplantation, concluded the researchers.

"With the increasing age of the population, diabetes will increase in prevalence and the demand for new treatment paradigms will become more pressing," said Dr. Camillo Ricordi, Diabetes Research Institute, University of Miami, Miami, FL. "Use of an anti-oxidant compound to combat immune rejection could be an effective method for overcoming obstacles to the advancement of cell therapy for diabetes."

Ref : http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-ct-1616_adin_et_al

Antioxidant compound could be effective to combat immune rejection after islet transplantation