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Study Presented at AHA Details How Diabetes Drives Extra Heart Attack Damage

Mechanism Suggests New Treatment Approach for Terrible Combination of Ailments

Tuesday, November 11, 2008

High Blood Sugar Causes Heart Muscle Cells To Self-Destruct

Researchers have found a better explanation for why heart attacks do more damage in patients with diabetes, according to a study presented at the 2008 Scientific Sessions of the American Heart Association.

Nearly 21 million Americans have diabetes, a disease where patients’ cells cannot efficiently take in dietary sugar, causing it to build up in the blood. In part because diabetes increases inflammation that causes clogs in blood vessels, diabetic patients are twice as likely to have a heart attack or stroke. In addition, heart attacks in people with diabetes do more tissue damage and are more likely to result in death. 

A number of clinical studies have shown that the pumping strength of the left ventricle, a key chamber of the heart, is significantly weakened (cardiomyopathy) in diabetic patients compared with non-diabetic patients by mechanisms that cause heart muscle cells to self-destruct. What has been missing is a plausible theory on the relationship between diabetes and any of the factors known to bring about the death of heart muscle cells.

In the current study, the work centers around an enzyme called extracellular signal-regulated kinase 5 (ERK-5), which protects blood vessels in healthy adults by opening up blood vessels and blocking inflammation related to atherosclerosis. His team also showed in past work that molecules called advanced glycation end products (AGEs), produced in greater levels by patients with diabetes, sabotage ERK5 by encouraging the attachment to it of a small ubiquitin-related modifier (SUMO). 

As a protein used by cells to fine-tune their control over proteins, a SUMO tag may, under normal conditions, extend a key protein’s lifespan, or cause it to move from one part of the cell to another. In a recent study, however, researchers found that AGEs induce ERK5-SUMOylation as part of heart disease in diabetics, driving inflammation and narrowing blood vessels.

In the paper presented at AHA this year, the team found that ERK-5 SUMOylation also accelerates the damage caused by heart attacks in diabetic hearts by increasing heart muscle cell death (apoptosis) in diabetic heart attack survivors, which in turn weakens left ventricle pumping strength.

“Our current study is important because it provides early proof that ERK-5 is a key molecule involved in the ability of diabetes to worsen heart attack damage,” said Jun-ichi Abe, M.D., Ph.D., associate professor within the Aab Cardiovascular Research Center (CVRI) at the University of Rochester Medical Center. “With this information in hand, we are now looking for drug candidates that can shut down SUMOylation in the endothelial cells lining blood vessels, and in heart muscle cells, of diabetic patients, or that can turn up targets of ERK-5 activation in those cells.”

In experiments where key molecules were used to shut down the SUMOylation of ERK-5, the hearts of diabetic mice saw dramatic increases in pumping strength and in heart muscle tissue integrity, while non-diabetic mice saw little change. These data suggested the importance of the ability of ERK-5 SUMOylation to switch off ERK-5, which would otherwise signal to turn on cardio-protective genes.

The team also found that ERK-5 SUMOylation was significantly increased after heart attacks in diabetic mice. In addition, the data strongly suggested that the activation of a relative of ERK-5, called MEK-5, known to inhibit diabetes-related ERK-5 SUMOylation, was cardioprotective.

Along with Abe, Chen Yan, Bo Ding, Chang-Hoon Woo, Carlos Molina, Tetsuro Shishido and Carolyn McClain contributed to the work within the CVRI, along with Jay Yang, professor of Anesthesiology at Columbia University. This work is supported by grants from the America Heart Association and the National Institutes of Health. 

“Our work argues strongly that ERK-5, and the manipulation of it, will be a vital part of future treatment for heart disease in diabetics,” Abe said. “Experiments already underway in our lab seek to identify the molecular mechanisms by which high blood sugar causes the SUMOylation of ERK-5.”

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