title: Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury.
abstract: OBJECTIVE
  We previously reported that cardiac-restricted deletion of focal adhesion kinase (FAK) exacerbated myocyte death following ischemia/reperfusion (I/R). Here, we interrogated whether targeted elevation of myocardial FAK activity could protect the heart from I/R injury.
  
  
  RESULTS
  Transgenic mice were generated with myocyte-specific expression of a FAK variant (termed SuperFAK) that conferred elevated allosteric activation. FAK activity in unstressed transgenic hearts was modestly elevated, but this had no discernable effect on anabolic heart growth or cardiac function. Importantly, SuperFAK hearts exhibited a dramatic increase in FAK activity and a reduction in myocyte apoptosis and infarct size 24 to 72 hours following I/R. Moreover, serial echocardiography revealed that the transgenic mice were protected from cardiac decompensation for up to 8 weeks following surgery. Mechanistic studies revealed that elevated FAK activity protected cardiomyocytes from I/R-induced apoptosis by enhancing nuclear factor-κB (NF-κB)-dependent survival signaling during the early period of reperfusion (30 and 60 minutes). Moreover, adenoviral-mediated expression of SuperFAK in cultured cardiomyocytes attenuated H(2)O(2) or hypoxia/reoxygenation-induced apoptosis, whereas blockade of the NF-κB pathway using a pharmacological inhibitor or small interfering RNAs completely abolished the beneficial effect of SuperFAK.
  
  
  CONCLUSIONS
  Enhancing cardiac FAK activity attenuates I/R-induced myocyte apoptosis through activation of the prosurvival NF-κB pathway and may represent a novel therapeutic strategy for ischemic heart diseases.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, 27599, USA.
authors.forename: Zhaokang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Laura A
authors.initials: LA
authors.lastname: DiMichele
authors.forename: Zeenat S
authors.initials: ZS
authors.lastname: Hakim
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mack
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D016328:NF-kappa B; D006861:Hydrogen Peroxide; D051416:Focal Adhesion Protein-Tyrosine Kinases