'Missing culprit' in heart failure identified

03/23/2015
Photo: Presure compared

Effects of pressure overload as seen in the image in the upper right corner. By contrast, mice with intact PDF-9 genes developed enlarged, dilated hearts captured here by walls that are stretched far apart from each other, as shown in the lower left corner; © Johns Hopkins Medicine

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, described March 18 in the journal Nature, reveal that an enzyme called PDE-9 interferes with the body's natural "braking" system needed to neutralize stress on the heart. The experiments demonstrate that the enzyme wreaks mischief 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 markedly elevated in patients with heart failure – evidence that PDE-9 is a multitasking "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 separate mechanisms, or signaling pathways. Activated by two different chemicals – nitric oxide and natriuretic peptide – each pathway produces cGMP, which in turn stimulates the all-important heart muscle protector PKG. Most cases of heart failure, the researchers say, are fueled by breakdowns in both.

"The existence of two separate pathways with overlapping but distinct functions is nature's insurance policy, a fail-safe redundancy to ensure that should one pathway falter, the other one can compensate and maintain heart muscle function," says senior investigator Dr. David Kass, professor of medicine at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute.

Nearly a decade ago, a team led by Kass identified the culprit responsible for breakdown in one of the signaling pathways, an enzyme called PDE-5 – also known to cause erectile dysfunction – and ever since then scientists have searched for the second "offender" that causes glitches in the other pathway. The discovery of PDE-9 provides that long-sought "break in the case," the team says.

"Like a play with multiple characters, heart muscle function is the result of a complex but perfectly synchronized interaction of several proteins, enzymes and hormones," says lead investigator Dong Lee, M.S., Ph.D., a cardiology research associate at the Johns Hopkins University School of Medicine. "Our findings reveal that, like two subplots that converge in the end of the play, PDE-5 and PDE-9 are independent rogue operators, each leading to heart muscle damage but doing so through different means."

MEDICA-TradeFair.com; Source: Johns Hopkins Medicine

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