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Inhibiting RAGE Holds Promise for Heart Attack Patients

Ravichandran Ramasamy, PhD

Ravichandran Ramasamy, PhD, Assistant Professor of Surgical Science at Columbia University College of Physicians & Surgeons, has demonstrated that a recently discovered method of reducing vascular complications in diabetics can also protect the hearts of non-diabetics during and after myocardial infarction (heart attack). Dr. Ramasamy's research could lead to treatments that significantly improve patients' recovery time and decrease the rate of heart failure following a heart attack. The findings were published earlier this year in the journal Circulation.

Dr. Ramasamy's research builds on studies conducted in the early 1990s, when researchers discovered AGE (advanced glycation end product) molecules, which are involved in the complications of diabetes. AGE molecules form when a diabetic's excess blood sugar (glucose) combines with fats and proteins in the bloodstream, a process similar to the chemical reaction of sugar, fat, and protein that browns food during cooking.

AGE molecules can accumulate in every tissue of the body. When they bind to active receptors on blood vessel walls, called RAGE (receptors for advanced glycation end products), the acronym becomes apt: The binding of AGE molecules to receptors produces inflammation and weakening of the blood vessel walls, disturbing the cells' normal cell function. This inflammatory process contributes to complications of diabetes such as impaired wound healing, atherosclerosis, and vascular dysfunction.

The discovery of the AGE/RAGE interaction allowed researchers to understand one way that high blood sugar levels can lead to diabetic complications. It also enabled them to find a solution. Introducing a decoy receptor called sRAGE (soluble RAGE) into laboratory animals, researchers found that the decoy prevented the RAGE receptors on blood vessel walls from becoming activated. This discovery has tremendous implications for preventing and treating diabetic cardiovascular complications, including dysfunction in the heart.

Now Dr. Ramasamy has discovered that RAGE also plays a part in heart attacks even when diabetes is not present. During heart attacks, energy availability is a significant factor in determining how well and how quickly a patient's heart will recover. Dr. Ramasamy, who had been studying metabolic processes involved in heart attacks and heart failure, found that changed metabolism of glucose, is a key culprit to slow recovery after heart attack.

In heart attacks, energy is often unavailable because glucose, critical for generating energy in any system, is diverted through a different enzymatic pathway, the aldose reductase pathway. Use of this pathway not only reduces the ability of the heart to generate energy, but also creates a chain reaction that eventually leads to the formation of AGE molecules and ultimately, conditions for the detrimental interaction of AGE and RAGE. "Under the conditions of myocardial infarction, increased glucose is taken up by the aldose reductase pathway and converted to sorbitol, which is then converted to fructose," says Dr. Ramasamy. The reaction doesn't stop - it leads to the formation of some of the precursors for AGE, ultimately becoming a pipeline for more AGE to be generated. "And once the receptors start interacting with AGE," he says, "the process gives rise to increased generation of free radicals and associated degeneration of mitochondrial proteins. As a consequence of injury to the mitochondria, energy production goes down, leading to increased cell injury and death."

Dr. Ramasamy's research in the laboratory has demonstrated that introducing the decoy receptor sRAGE allows damaged hearts to recover more quickly. "When we attenuate the AGE/RAGE process by introducing soluble RAGE in rats and mice, we see immense protection of the heart and its mitochondria. This is a very important finding in terms of how sRAGE can play a role in mediating injury to the heart, even in the absence of diabetes," Dr. Ramasamy emphasizes.

The study of RAGE and its surprising relevance in non-diabetic heart attacks complements Dr. Ramasamy's previous research, which found that inhibiting the aldose reductase enzyme during myocardial infarction was also effective in reducing damage to both diabetic and non-diabetic hearts.

This research was published in Circulation, 2006: vol. 113, pp. 1226-1234.

• Read more about Dr. Ramasamy's research