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Enriched FAK Activity Protects Cardiomyocytes from Heart Attack Damage

By BiotechDaily International staff writers
Posted on 22 Mar 2012
Cardiovascular disease researchers have identified a protein in cardiomyocytes that when expressed at high levels protects heart cells from damage caused during myocardial infarction due to the sudden loss of oxygen.

Investigators at the University of North Carolina (Chapel Hill, USA) had shown previously that deletion of the enzyme focal adhesion kinase (FAK) exacerbated myocyte death following heart attack. FAK is a highly conserved, cytosolic, protein-tyrosine kinase involved in cell-cell and cell-matrix interaction and responsible for formation of the focal adhesion complex. It is widely expressed throughout development.

In the current study, the investigators examined the effect of enriched FAK activity on cardiomyocytes during and after heart attack (ischemia/perfusion) in a mouse model. To this end, they created a line of mice genetically engineered to express a highly active form of FAK (SuperFAK) in their cardiomyocytes.

They reported in the March 1, 2012, online edition of the journal Arteriosclerosis, Thrombosis and Vascular Biology that FAK activity in unstressed transgenic hearts was modestly elevated, but this had no discernible effect on anabolic heart growth or cardiac function. On the other hand, SuperFAK hearts exhibited a dramatic increase in FAK activity and a reduction in myocyte apoptosis and infarct size 24 to 72 hours following ischemia/perfusion.

Mechanistic studies revealed that elevated FAK activity protected cardiomyocytes from ischemia/perfusion-induced apoptosis by enhancing nuclear factor-kappaB (NF-kappaB)-dependent survival signaling during the early period of reperfusion (30 and 60 minutes). Moreover, adenoviral-mediated expression of SuperFAK in cultured cardiomyocytes attenuated H2O2 or hypoxia/reoxygenation-induced apoptosis. Blockade of the NF-kappaB pathway using a pharmacological inhibitor or small interfering RNAs completely abolished the beneficial effect of SuperFAK.

"This study shows that we can enhance existing cell survival pathways to protect heart cells during a heart attack," said senior author Dr. Joan Taylor, associate professor of pathology and laboratory medicine at the University of North Carolina. "We thought if we could activate FAK to a greater extent, then we could better protect those heart cells."

"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 Dr. Taylor. "Negative feedback loops are important because they "reset" the system."

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University of North Carolina


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