title: Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism.
abstract: TLRs play a critical role in the induction of innate and adaptive immunity. However, TLRs have also been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We have reported that TLR4(-/-) mice show decreased myocardial injury following I/R; however, the protective mechanisms have not been elucidated. We examined the role of the PI3K/Akt signaling pathway in TLR4(-/-) cardioprotection following I/R injury. TLR4(-/-) and age-matched wild-type (WT) mice were subjected to myocardial ischemia for 45 min, followed by reperfusion for 4 h. Pharmacologic inhibitors of PI3K (wortmannin or LY294002) were administered 1 h before myocardial I/R. Myocardial infarct size/area at risk was reduced by 51.2% in TLR4(-/-) vs WT mice. Cardiac myocyte apoptosis was also increased in WT vs TLR4(-/-) mice following I/R. Pharmacologic blockade of PI3K abrogated myocardial protection in TLR4(-/-) mice following I/R. Specifically, heart infarct size/area at risk was increased by 98% in wortmannin and 101% in LY294002-treated TLR4(-/-) mice, when compared with control TLR4(-/-) mice. These data indicate that protection against myocardial I/R injury in TLR4(-/-) mice is mediated through a PI3K/Akt-dependent mechanism. The mechanisms by which PI3K/Akt are increased in the TLR4(-/-) myocardium may involve increased phosphorylation/inactivation of myocardial phosphatase and tensin homolog deleted on chromosome 10 as well as increased phosphorylation/inactivation of myocardial glycogen synthase kinase-3beta. These data implicate innate immune signaling pathways in the pathology of acute myocardial I/R injury. These data also suggest that modulation of TLR4/PI3K/Akt-dependent signaling pathways may be a viable strategy for reducing myocardial I/R injury.
authors.affiliation: Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jim
authors.initials: J
authors.lastname: Kelley
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: I William
authors.initials: IW
authors.lastname: Browder
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002867:Chromones / Q000008:administration & dosage; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000008:administration & dosage; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051197:Toll-Like Receptor 4; D000077191:Wortmannin; C493487:Tlr4 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one