Protection Against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated Through a Phosphoinositide 3-Kinase-Dependent Mechanism
Document Type
Article
Publication Date
6-1-2007
Description
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-3β. 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.
Citation Information
Hua, Fang; Ha, Tuanzhu; Ma, Jing; Li, Yan; Kelley, Jim; Gao, Xiang; Browder, I. William; Kao, Race L.; Williams, David L.; and Li, Chuanfu. 2007. Protection Against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated Through a Phosphoinositide 3-Kinase-Dependent Mechanism. Journal of Immunology. Vol.178(11). 7317-7324. https://doi.org/10.4049/jimmunol.178.11.7317 PMID: 17513782 ISSN: 0022-1767