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University Of Pittsburgh Researchers Use Gene Therapy To Prevent Cardiac Rupture And Prolong Life In Mouse Model Of Heart Attack

DALLAS, November 16, 2005 — A University of Pittsburgh research team has found that gene vector carrying an inhibitor of metalloproteinase-2 (MMP-2), a protein shown to stimulate adverse healing in heart tissue after a heart attack, protected experimental mice against further cardiac damage and subsequent death.

Furthermore, the benefits correlated with a partial restoration of the normal ratios between metalloproteinase-2 and its specific inhibitor, known as tissue inhibitor of metalloproteinase-2 (TIMP-2). These results are being reported at the annual meeting of the American Heart Association, Nov. 13-16 in Dallas. Further studies are needed to determine the mechanism of this protective effect.

“Induction of metalloproteinases has been shown to contribute to adverse remodeling of cardiac tissue after myocardial infarction," according to Charles McTiernan, Ph.D., research assistant professor in the division of cardiology at the University of Pittsburgh School of Medicine . “It has been hypothesized that supplementing post-MI tissue with TIMP-2 can normalize the balance of metalloproteinases and their specific inhibitors and protect against the damage of myocardial infarction.”

To determine if gene therapy could be used to improve outcomes following a heart attack, Dr. McTiernan and his coworkers gave one group of mice with experimental myocardial infarctions (MI) an injection of viral particles containing the TIMP-2 gene and compared their outcomes to untreated MI and control mice. The investigators then assessed the left ventricular size and function of the surviving mice seven days after their myocardial infarction and also measured MMP-2 and -9 and TIMP-1 and -2 protein levels.

Among the mice that died, the major cause of death was rupturing of cardiac tissue. Among the mice that survived, left ventricular systolic function was not different between the treated and untreated MI mice. However, levels of MMP-2 and - 9 were highest in the untreated MI group. TIMP-1 levels were higher in all MI hearts compared to controls, but there was no significant difference between the treated and untreated MI groups. TIMP-2 levels, however, were highest in the treated MI group. Overall, 34 mice survived till the end of the study period, and survival was significantly better in the TIMP-2-treated group compared with the untreated MI group (56 percent vs. 34 percent respectively, p< 0.02).

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