New Targets for Heart Therapies Possible Via Newly Discovered Heart Mechanism
The language used by the cells is a major surprise because it employs extremely reactive chemicals that are better known for the harm they do than for basic cell functions, say the researchers.
The authors mechanically stretched individual heart cells in order to simulate the behavior of the heart when it fills with blood with each heartbeat. They discovered, to their surprise, that the stretch generates a small burst of reactive oxygen species (ROS), also known as free radicals. While free radicals are commonly considered detrimental to the cell and are the target of anti-oxidants (substances that help to stop deterioration), the authors found that the small, controlled burst of ROS activates normal calcium signals that regulate contraction of the healthy heart.
In contrast, a larger, uncontrolled burst of ROS was detrimental. The uncontrolled burst of ROS in those cells caused the essential calcium signaling to go awry, which can disrupt the normal heart rhythm and trigger arrythmias.
By defining the mechanisms involved in this process, this study provides new targets for the treatment of heart disease, the researchers concluded.
"We have unmasked a signal that would otherwise be invisible," said W. Jonathan Lederer, MD, PhD, co-author and director of the University of Maryland Center for Biomedical Engineering and Technology (BioMET). In 1993, Lederer and colleagues discovered calcium "sparks," the elementary calcium signals that regulate contraction of the heart. Then in 2009, Lederer and Christopher Ward, MD, associate professor, University of Maryland School of Nursing and co-author of the Science paper, with a group from Oxford University, first identified that stretching a heart cell could activate calcium sparks. However the molecular mechanism behind this process, and the implications it held for disease, remained elusive until the present work.
Discovery of such molecular signaling is important for two reasons. First, it helps heart physiologists better understand basic physiologic heart workings. "We can now look at a whole heart phenomenon but study it at a single cell level and get down to what is really happening in the individual heart cell," says co-author Benjamin Prosser, PhD, postdoctoral fellow, BioMET. "We think we have identified a mechanism that occurs in every heart cell with every heartbeat, and that is fundamental to the regulation of calcium release in the heart."
In a larger context, says Prosser, "We have discovered a mechanism that is contributing to oxidative stress [in the heart]." It is well established that excess ROS production can cause oxidative stress, which negatively impacts the function of the heart. However the source of this excess ROS is still debated. According to Ward, "Our team''s discoveries could be especially profound for studies of muscular dystrophy and other forms of heart disease. We believe that this uncontrolled production of ROS is important across any failing heart problem. We intend to test that theory."
Enabling the discoveries of Prosser et al. was their invention and development of a new biological adhesive, MyoTakâ„¢. The biological "glue" allowed the researchers to attach single heart cells to equipment designed to study the mechanical properties of the cell, a new technology that will now be marketed to researchers worldwide. Two companies have licensed the biological glue: IonOptix (Milton, Mass.) and World Precision Instruments (Sarasota, Fla.)
The Science paper by Prosser, Ward, and Lederer is, "X-ROS Signaling: Rapid Mechano-Chemo Transduction in Heart," Sept. 9, 2011.