Transplanted Gene Repairs Chronic Heart Damage in Rat Model

Cardiovascular disease researchers have used advanced gene therapy techniques to repair damaged heart muscle in a rat model of chronic heart failure.

Investigators at Thomas Jefferson University (Philadelphia, PA, USA) worked with a peptide called beta-ARKct, which had been shown previously in transgenic models and short-term gene transfer experiments to repair the damage caused by chronic heart failure. Beta-ARKct inhibits the activation of G protein–coupled receptor kinase 2 (GRK2), an enzyme that is overexpressed in damaged heart tissue.

In the current study, the investigators placed the gene for beta-ARKct in viral vector constructed from recombinant-adeno-associated virus serotype 6 (rAAV6). The viral vector was injected directly into the heart muscles of rats suffering from chronic heart failure. The rats were separated into five experimental groups. Two groups received beta-ARKct (one of the groups also received the beta-blocker metoprolol), two groups received a green fluorescent protein (again, one group also received metoprolol), and the fifth group received a saline solution.

Results published in the December 22, 2008, online edition of the journal Circulation revealed that the beta-ARKct gene was expressed in the animals' left ventricle for at least 12 weeks after delivery. The peptide significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the animals, including normalization of cardiac beta-adrenergic receptor signaling. Addition of metoprolol neither enhanced nor decreased the beneficial effects of beta-ARKct, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle. The rats that received the green fluorescent protein or saline alone experienced more deterioration of cardiac function during the course of the study.

"The theory is that by inhibiting G protein–coupled receptor kinase 2, the heart will recover partially due to reversal of the desensitization of the beta-adrenergic receptors,” said senior author Dr. Walter J. Koch, professor of medicine at Thomas Jefferson University. "The expression of beta-ARKct leads to a negative neurohormonal feedback that prevents the heart from continuing on the downward slope during heart failure. This was one novel finding of the study.”

"Our data show that beta blockers and the beta-ARKct peptide are compatible and can be given together,” said Dr. Koch. "Although beta blockers are effective at stopping the downward progression of the disease, they do not reverse the damage already done. That is where the Beta-ARKct gene therapy comes in.”

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