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Conditional knockout of myocyte focal adhesion kinase abrogates ischemic preconditioning in adult murine hearts.

Abstract：

BACKGROUND:Our laboratory has previously demonstrated the importance of a cytoskeletal-based survival signaling pathway using in vitro models of ischemia/reperfusion (IR). However, the importance of this pathway in mediating stress-elicited survival signaling in vivo is unknown. METHODS AND RESULTS:The essential cytoskeletal signaling pathway member focal adhesion kinase (FAK) was selectively deleted in adult cardiac myocytes using a tamoxifen-inducible Cre-Lox system (α-MHC-MerCreMer). Polymerase chain reaction (PCR) and Western blot were performed to confirm FAK knockout (KO). All mice were subjected to a 40-minute coronary occlusion followed by 24 hours of reperfusion. Ischemic preconditioning (IP) was performed using a standard protocol. Control groups included wild-type (WT) and tamoxifen-treated α-MHC-MerCreMer+/-/FAK(WT/WT) (experimental control) mice. Infarct size was expressed as a percentage of the risk region. In WT mice IP significantly enhanced the expression of activated/phosphorylated FAK by 36.3% compared to WT mice subjected to a sham experimental protocol (P ≤ 0.05; n = 6 hearts [sham], n = 4 hearts [IP]). IP significantly reduced infarct size in both WT and experimental control mice (43.7% versus 19.8%; P ≤ 0.001; 44.7% versus 17.5%; P ≤ 0.001, respectively). No difference in infarct size was observed between preconditioned FAK KO and nonpreconditioned controls (37.1% versus 43.7% versus 44.7%; FAK KO versus WT versus experimental control; P=NS). IP elicited a 67.2%/88.8% increase in activated phosphatidylinositol-3-kinase (PI3K) p85/activated Akt expression in WT mice, but failed to enhance the expression of either in preconditioned FAK KO mice. CONCLUSIONS:Our results indicate that FAK is an essential mediator of IP-elicited cardioprotection and provide further support for the hypothesis that cytoskeletal-based signaling is an important component of stress-elicited survival signaling.

journal_name

J Am Heart Assoc

journal_title

Journal of the American Heart Association

authors

Perricone AJ,Bivona BJ,Jackson FR,Vander Heide RS

doi

10.1161/JAHA.113.000457

subject

Has Abstract

pub_date

2013-09-30 00:00:00

pages

e000457

issue

issn

2047-9980

pii

jah3323

journal_volume

pub_type

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Conditional knockout of myocyte focal adhesion kinase abrogates ischemic preconditioning in adult murine hearts.