PDE-9 Enzyme Is Molecular Culprit in Breakdown of Second Signaling Pathway Triggering Heart Failure; Drugs Inhibiting PDE-9 Already in Testing for Alzheimer’s

Working with lab animals and human heart cells, scientists from Johns Hopkins and other institutions have identified what they describe as "the long-sought culprit" in the mystery behind a cell-signaling breakdown that triggers heart failure. The condition, which affects nearly 6 million Americans and 23 million people worldwide, is marked by progressive weakening and stiffening of the heart muscle and the organ's gradual loss of blood-pumping ability. The research results, published online on March 18, 2015 in Nature, reveal that an enzyme called PDE-9 (image) interferes with the body's natural "braking" system needed to neutralize stress on the heart. The title of the Nature article is “Phosphodiesterase 9A Controls Nitric-Oxide-Independent cGMP and Hypertrophic Heart Disease.” The experiments demonstrated that the PDE-9 enzyme wreaks havoc by gobbling up a signaling molecule, cGMP, which normally stimulates the production of a heart-protective protein called PKG, known to shield the heart muscle from the ravages of disease-causing stress, such as long-standing high blood pressure. Naturally found in the gut, kidneys, and brain, PDE-9 is already a prime suspect in neurodegenerative conditions such as Alzheimer's, the researchers say. But the new study shows the enzyme's footprints are also present in heart cells and are markedly elevated in patients with heart failure -- evidence that PDE-9 is a multi-tasking "offender" and a key instigator of heart muscle demise, the researchers say. To understand the enzyme's role, the scientists exploited the knowledge that heart muscle health is safeguarded by two signaling pathways.
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