Aldose Reductase Inhibition Prevents Endotoxin-Induced Cardiomyopathy and Sepsis

Aruni Bhatnagar, Ph.D., University of Louisville and
Satish K. Srivastava, Ph.D., University of Texas Medical Branch
P01ES011860 and P30ES006676

Sepsis is characterized by an overreaction of the immune system in response to a severe bacterial infection. Death usually occurs from heart or other major organ failure. The incidence of sepsis is on the rise; a study conducted by the Centers for Disease Control and Prevention found that the number of cases has nearly tripled in the past couple of decades-82.7 cases/100,000 Americans in 1979 to 240.4 cases/100,000 in 2000. Much of the reason for this dramatic increase is attributed to antibiotic-resistant bacteria, caused by the overuse of antibiotics, and conditions resulting in a weakened immune system.

Now NIEHS-supported researchers at the University of Texas Medical Branch report that by blocking the activity of the enzyme aldose reductase in laboratory mice, they can prevent the development of sepsis and the resulting heart failure brought on from endotoxin exposure. The researchers blocked aldose reductase activity either through administration of sorbinil or small interfering RNA. Endotoxin administration caused large increases in serum and cardiac cytokines; this response was suppressed when aldose reductase activity was inhibited. Aldose reductase inhibition increased survival in mice following lethal doses of endotoxin.

Previous work by this team has shown that blocking aldose reductase reduced the inflammation-driven processes in colorectal cancer and diabetes. A compound very similar to sorbinil is now undergoing phase III clinical trials for use in diabetes.

Citation: Ramana KV, Willis MS, White MD, Horton JW, DiMaio JM, Srivastava D, Bhatnagar A, Srivastava SK. Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition. Circulation. 2006 Oct 24;114(17):1838-46.