The study, in which mice were bred to make a supercharged version of the protein focal adhesion kinase, or FAK, appeared March 1 in the online edition of the journal Arteriosclerosis, Thrombosis and Vascular Biology.
Following heart attack, heart cells are stressed due to lack of oxygen. When SuperFAK (in green) is expressed in the heart, it is further activated and protects heart cells from oxidative stress (in red). Credit: Joan Taylor, Ph.D
"This study shows that we can enhance existing cell survival pathways to protect heart cells during a heart attack," said Joan Taylor, PhD, associate professor in UNC's department of pathology and laboratory medicine. Taylor added that the findings could lead to new treatment approaches for heart attacks and may have broad implications for scientists seeking to manipulate the body's natural defensive systems.
During a heart attack, oxygen-deprived heart cells emit signals that activate the usually inert protein FAK, like the cry of a damsel in distress awakening her sleeping knight. If the gallant FAK arrives in time, it can save the cell and reduce permanent damage to the heart.
Taylor and her colleagues were intrigued by FAK's protective abilities. "We thought if we could activate FAK to a greater extent, then we could better protect those heart cells," said Taylor. Based on their previous studies that defined the signals induced by FAK in heart cells, they reasoned that expression of FAK set to an "always-on" position would eventually suffer uncontrolled inflammation and heart failure. "Simply having more of a good thing isn't always better," said Taylor. "The dynamics of the protein's activities are important to appropriately transmitting those survival signals."
The researchers then adjusted their formula to create a new protein they called "SuperFAK." To enhance its protective abilities without the harmful side effects, SuperFAK was primed for activation—ready to rush to the scene at the slightest provocation from stressed heart cells—but remained under the control of the mice's natural feedback systems that would shut it off when the crisis passed.
Mice with SuperFAK showed a much stronger FAK response during a heart attack than mice with the natural protein, and three days later had about 50 percent less heart damage. Critically, SuperFAK deactivated at the appropriate time, so the eight-week follow-up revealed no detrimental effects.
The findings offer evidence that, rather than simply activating or de-activating key proteins, researchers can benefit from a more nuanced approach that taps into the body's natural feedback loops. "I think folks could use this idea to exploit mutations in other molecules—by thinking about how to modify the protein so that it can be under natural controls," said Taylor. "Negative feedback loops are important because they 'reset' the system."
The findings also may help researchers augment FAK in patients undergoing chemotherapy. Some chemotherapy drugs are known to break down FAK, leaving patients' hearts more vulnerable to damage.
Co-authors included Zhaokang Cheng, Laura A. DiMichele, Zeenat S. Hakim, Mauricio Rojas and Christopher P. Mack. The research was supported by grants from the National Institutes of Health and the American Heart Association.
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