Journal article
Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury
Arteriosclerosis, thrombosis, and vascular biology, Vol.32(4), pp.924-933
04/2012
Handle:
https://hdl.handle.net/2376/109204
PMID: 22383703
Abstract
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.
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.
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.
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Details
- Title
- Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury
- Creators
- Zhaokang Cheng - Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, 27599, USALaura A DiMicheleZeenat S HakimMauricio RojasChristopher P MackJoan M Taylor
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.32(4), pp.924-933
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- R01 HL081844-03 / NHLBI NIH HHS R01 HL081844-07 / NHLBI NIH HHS R01 HL081844-08 / NHLBI NIH HHS R01 HL081844-02 / NHLBI NIH HHS R01 HL071054 / NHLBI NIH HHS R01 HL109607 / NHLBI NIH HHS R01 HL081844-05A1 / NHLBI NIH HHS HL-081844 / NHLBI NIH HHS HL-071054 / NHLBI NIH HHS R01 HL081844-04 / NHLBI NIH HHS R01 HL081844-01 / NHLBI NIH HHS R01 HL081844-06 / NHLBI NIH HHS R01 HL081844 / NHLBI NIH HHS
- Identifiers
- 99900547184001842
- Language
- English
- Resource Type
- Journal article