Gene Regulation May Prevent Cardiac Hypertrophy

Mouse experiment targets PDE5 gene expression in heart muscle to prevent heart remodeling

FRIDAY, Oct. 22 (HealthDay News) -- Regulating expression of the phosphodiesterase type 5 (PDE5) gene in heart muscle cells can reverse maladaptive heart remodeling, such as cardiac hypertrophy, caused by sustained pressure overloads, according to the results of a mouse study published online Oct. 20 in the Journal of the American College of Cardiology.

Manling Zhang, M.D., of the Johns Hopkins University School of Medicine in Baltimore, and colleagues generated mice with doxycycline-controllable myocyte PDE5 gene expression. The transgenic mice and a control group of normal mice were then subjected to sustained heart pressure overload by aortic banding.

The researchers found that, under the pressure overload, the transgenic mice exhibited eccentric heart remodeling, maladaptive molecular signaling, depressed function, and amplified fibrosis. After establishing this cardiomyopathic state, the researchers gave the transgenic mice doxycycline to suppress PDE5 expression in the myocytes, which enhanced cyclic guanosine monophosphate (cGMP) and downstream protein kinase G (PKG) pathway activity and reversed the remodeling and other maladaptive responses, despite the sustained pressure overload. Sildenafil, which is known to inhibit PDE5, was also effective.

"These data strongly support a primary role of myocyte PDE5 regulation to myocardial pathobiology and PDE5 targeting therapy in vivo and reveal a novel mechanism of myocyte-orchestrated extracellular matrix remodeling via PDE5/cyclic guanosine monophosphate-PKG regulatory pathways," the authors write.

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Jeff Muise

Jeff Muise

Published on October 22, 2010

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