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* Department of Surgery and
Department of Internal Medicine, East Tennessee State University, Johnson City, TN 37614; and
Animal Model Research Center, Nanjing University, Nanjing, China
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-3
. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health R01 HL071837 to (C.L.). This work was also supported in part by National Institutes of Health GM53552 (to D.L.W.); East Tennessee State University Research Development Committee grant (to T.H.); and National Gongguan Project of China (NGGPOC) 2001BA710B (to X.G.).
2 Address correspondence and reprint requests to Dr. Chuanfu Li, Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575. E-mail address: Li{at}ETSU.EDU
3 Abbreviations used in this paper: I/R, ischemia/reperfusion; GSK, glycogen synthase kinase; IA/RA, infarct area vs risk area; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RA/LV, risk area vs left ventricle; TTC, triphenyltetrazolium chloride; WT, wild type.
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