Cell signaling discovery yields heart disease clues

September 23, 2005

PORTLAND, Ore. - A pulsing heart cell is giving Oregon Health & Science University researchers insight into how it sends and receives signals, and that's providing clues into how heart disease and other disorders develop.

In a study appearing in today's edition of Nature, John Scott, Ph.D., a Howard Hughes Medical Institute investigator and senior scientist at OHSU's Vollum Institute, found that heart muscle cells become enlarged when an intricate intracellular signaling pathway regulated by a messenger molecule called muscle-specific A-kinase anchoring proteins, or mAKAPs, is perturbed.

The cells' growth, known as cardiomyocyte hypertrophy, can lead to congestive heart failure and other forms of cardiovascular disease, which affect more than 70 million Americans and cause about 1.4 million deaths each year.

A cell communicates with another cell by sending over a messenger molecule, typically a hormone, which activates a secondary regulatory messenger molecule - cyclic AMP (cAMP) - within a particular compartment in the recipient cell. This causes cAMP to stimulate an enzyme that triggers the activity of proteins involved in altering a cell's physiology and governing other biochemical events.

According to Scott, mAKAPs tether the enzyme, called protein kinase A (PKA), to particular locations in the cell.

"Hypertrophy is a fairly good laboratory model for certain forms of heart failure, and the PKA signaling pathway is perturbed in certain cases of heart disease," said Scott, whose laboratory was the among the first in the world to track AKAP interaction. "That's why this study may have a high translational and clinical impact."

According to the study, the mAKAP signaling system has been linked to excessive heart cell enlargement, which increases the potential for heart disease. One technique involves using drugs, such as a growth hormone, to activate a molecule known as ERK5, which suppresses the enzyme phosphodiesterase. This causes cAMP, which is normally metabolized by phosphodiesterase, to accumulate in certain parts of the cell.

"Many, many phosphodiesterases are drug targets," Scott noted. "So potentially, drugs that could target this particular phosphodiesterase, particularly, could be very useful. That's still a long way away, but that's where the work will go. Plus, it fits into a large body of work implicating these molecules as markers for certain forms of heart disease. Heart rate, for example, is controlled by calcium, and there's some level of regulation by cyclic AMP as well."

To show the signal transduction process in a heart muscle cell, Scott and his colleagues used a fluorescent microscope that captures protein molecules stained with various colored dyes to show PKA activity in a cell. In one set of images, captured over six minutes, a greenish-yellow ring appears to expand around the cell's nucleus before quickly shrinking.

"That's showing the rise in PKA activity, and the drop," Scott said.

Scott compares a cell to a highly organized city containing a variety of organizations serving particular functions, such as fire and police departments, an airport, a city hall and other entities. They all use one communication system, but information is delivered to, and interpreted by, each entity differently.

"The idea is that the cell is like this three-dimensional city, and at different times of the day, different things happen in the city," he explained. "This family of molecules we work on serves to pinpoint enzymes within three dimensions of the cell, and that's very important because it means that these enzymes act very locally. What the imaging data in this paper shows is that not only do they work in three dimensions, but there's this fourth dimension - time."

In addition, he said, "phosphodiesterase is a great drug target that could be something of importance in terms of pharmaceutical intervention at a later date."
-end-
The study was funded by the National Institutes of Health and the American Heart Association.

To access all OHSU news releases, visit www.ohsu.edu/news/

Oregon Health & Science University

Related Heart Disease Articles from Brightsurf:

Cellular pathway of genetic heart disease similar to neurodegenerative disease
Research on a genetic heart disease has uncovered a new and unexpected mechanism for heart failure.

Mechanism linking gum disease to heart disease, other inflammatory conditions discovered
The link between periodontal (gum) disease and other inflammatory conditions such as heart disease and diabetes has long been established, but the mechanism behind that association has, until now, remained a mystery.

New 'atlas' of human heart cells first step toward precision treatments for heart disease
Scientists have for the first time documented all of the different cell types and genes expressed in the healthy human heart, in research published in the journal Nature.

With a heavy heart: How men and women develop heart disease differently
A new study by researchers from McGill University has uncovered that minerals causing aortic heart valve blockage in men and women are different, a discovery that could change how heart disease is diagnosed and treated.

Heart-healthy diets are naturally low in dietary cholesterol and can help to reduce the risk of heart disease and stroke
Eating a heart-healthy dietary pattern rich in vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, vegetable oils and nuts, which is also limits salt, red and processed meats, refined-carbohydrates and added sugars, is relatively low in dietary cholesterol and supports healthy levels of artery-clogging LDL cholesterol.

Pacemakers can improve heart function in patients with chemotherapy-induced heart disease
Research has shown that treating chemotherapy-induced cardiomyopathy with commercially available cardiac resynchronization therapy (CRT) delivered through a surgically implanted defibrillator or pacemaker can significantly improve patient outcomes.

Arsenic in drinking water may change heart structure raising risk of heart disease
Drinking water that is contaminated with arsenic may lead to thickening of the heart's main pumping chamber in young adults, according to a new study by researchers at Columbia University Mailman School of Public Health.

New health calculator can help predict heart disease risk, estimate heart age
A new online health calculator can help people determine their risk of heart disease, as well as their heart age, accounting for sociodemographic factors such as ethnicity, sense of belonging and education, as well as health status and lifestyle behaviors.

Wide variation in rate of death between VA hospitals for patients with heart disease, heart failure
Death rates for veterans with ischemic heart disease and chronic heart failure varied widely across the Veterans Affairs (VA) health care system from 2010 to 2014, which could suggest differences in the quality of cardiovascular health care provided by VA medical centers.

Heart failure: The Alzheimer's disease of the heart?
Similar to how protein clumps build up in the brain in people with some neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, protein clumps appear to accumulate in the diseased hearts of mice and people with heart failure, according to a team led by Johns Hopkins University researchers.

Read More: Heart Disease News and Heart Disease Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.