NEW YORK (Reuters Health) - In myocytes isolated from failing human myocardium, gene therapy to inhibit beta-adrenergic receptor kinase (beta-ARK1) restores contractile function and beta-adrenergic responsiveness, according to new research findings. “Beta-ARK1 inhibition may represent a therapeutic strategy for human heart failure,” senior investigator Dr. Walter J. Koch and associates write in the April 6th issue of Circulation.
Dr. Koch, at Jefferson Medical College in Philadelphia, and his associates theorize that enhanced sympathetic nervous system activity and excessive catecholamine stimulation of beta-ARs lead to the characteristics of heart failure. Animal studies have shown that inhibition of beta-ARK1 translocation with a peptide containing beta-gamma subunits of G protein (beta-ARKct) reverses these changes.
The investigators obtained myocytes from 10 failing hearts explanted from patients undergoing heart transplantation. Cells from each patient were then infected with an adenoviral vector expressing beta-ARKct and green fluorescent protein (GFP).
During treatment with the beta-agonist isoproterenol, the velocities of contraction were significantly increased in the beta-ARKct expressing cells compared with uninfected cells (57.5% shortening per second versus 37.0% in control cells), as were rates of relaxation (43.8% lengthenings per second versus 27.5%).
Adenylyl cyclase activity and fractional shortenings were also enhanced in the beta-ARKct-expressing cells.
These findings “demonstrate an ultimate ‘proof of concept’” that beta-ARK1 inhibition improves clinical response in failing human myocytes, Dr. Koch’s team writes. Because the outlook for patients with end-stage heart failure remains grim, they hope that “further research ... will advance gene therapy as a viable option” for this condition.
Source: Circulation 2004;109:1590-1593. [ Google search on this article ]
MeSH Headings:Biological Therapy: Genetic Engineering: Genetic Techniques: Investigative Techniques: Myocardial Contraction: Therapeutics: Gene Therapy: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
