Sci. Aging Knowl. Environ., 15 October 2003
Vol. 2003, Issue 41, p. nw140
[DOI: 10.1126/sageke.2003.41.nw140]


Common Denominator

One protein connects three routes by which diabetes ravages hearts

Mary Beckman;2003/41/nw140

Key Words: PKC • Hexosamine • advanced glycation endproduct (AGE) • NF-{kappa}B • polyol • endothelial cells

Like a beaver dam that backs up a river into its tributaries, a crippled metabolic enzyme causes overflows upstream that spur cardiovascular disease in diabetics, new research shows. The results suggest that breaching the dam might be a new approach for preventing diabetes-related heart disease.

Diabetics have a two- to fourfold higher risk of heart attack than nondiabetics. Excess blood sugar damages blood vessels, and even conscientious diabetics have trouble controlling their blood sugar. Molecules produced by backups in four distinct biochemical pathways spur the cardiovascular problems. These pathways feed into the main metabolic stream by which the body breaks down sugar, so developmental biologist Michael Brownlee of the Albert Einstein College of Medicine in New York City and colleagues wondered whether a single downstream block could explain the phenomenon.

Extracting energy from sugar creates reactive oxygen species (ROS), which are toxic (see "The Two Faces of Oxygen"). In 2001, Brownlee and colleagues found that high sugar concentrations in cow aorta cell cultures, a model for human blood vessels, increases the production of ROS. ROS generation occurs far downstream of the spillover responsible for diabetes-related heart problems. The researchers postulated that if too much ROS corked the energy-generation pipeline, the tributaries might back up and slop heart-damaging metabolites over their banks. The scientists turned their attention to an enzyme called GAPDH, which acts in the process of energy generation at a point after the heart-debilitating pathways merge and before ROS are produced.

The researchers first tested whether the enzyme influences the buildup of heart-hurting metabolites by disrupting the production of GAPDH in bovine aorta cells cultured with normal or high concentrations of glucose. Loss of GAPDH in normal sugar concentrations caused the accumulation of as many metabolites in the three diabetic pathways they tested as high concentrations of glucose did. Additional experiments showed that high glucose concentrations caused GAPDH to acquire a chemical adornment that turns the enzyme off. When the researchers thwarted addition of the embellishment by tripping up the protein, PARP, that decorates GAPDH, they prevented metabolites from piling up.

Amounts of heart-flogging intermediates also ebbed in the presence of chemicals that reduce ROS quantities, suggesting that ROS somehow interfere with GAPDH's activity. ROS fracture DNA, and broken DNA revs up PARP, so the team investigated whether high glucose concentrations cause DNA to crack. They do, resulting in both split DNA and activated PARP. Together, the results suggest that ROS break DNA, which stimulates PARP; PARP turns off GAPDH, which allows the intermediates to back up. Therapies that sop up or drain ROS might prevent cardiovascular damage from overabundant metabolites, Brownlee says.

Endocrinologist Jane Reusch of the University of Colorado Health Sciences Center in Denver says that knowing what cellular molecule--ROS-sensitive PARP--is driving the diabetic complications "is really exciting." Drugs that combat ROS "are out there," she adds, speculating that they "seem liable to get fast-tracked" to clinical trials. With the dam in sight, researchers hope that cracking it might minimize the damage from diabetes's glucose flood.

--Mary Beckman

October 15, 2003
  1. X. Du et al., Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J. Clin. Invest. 112, 1049-1057 (2003). [CrossRef][Medline]
Citation: M. Beckman, Common Denominator. Sci. SAGE KE 2003 (41), nw140 (2003).

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