Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism

Ha, Tuanzhu; Fang, Hua; Liu, Xiang; Ma, Jing; McMullen, Julie R.; Shioi, Tetsuo; Izumo, Seigo; Kelley, Jim; Gao, Xiag; Browder, William; Williams, David L.; Kao, Race L.; Li, Chuanfu

doi:10.1093/cvr/cvn037

Cited by 155 publications

(173 citation statements)

References 37 publications

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“…For example, hearts isolated from rats pretreated with a low dose of LPS (0.5 mg/kg) 24 h before had a better preserved myocardial function after I/R compared with the saline-treated control hearts (18,105). Similar cardiac protection in LPS-treated animals was observed in vivo and in different animal models of I/R injury, such as rabbit (13,99), rat (18,88,106,138,155,166,167), and mice (48). The cardioprotective effect of LPS usually occurs between 12-24 h after the administration of LPS and is abolished by cycloheximide (106), suggesting a mechanism involving the de novo synthesis of cardioprotective proteins.…”

Section: Lps Preconditioning Against I/r Injurymentioning

confidence: 63%

“…Autopsy studies from patients who died of sepsis revealed minor apoptotic cell death in the heart, whereas there was profound lymphocyte and gastrointestinal epithelial cell death (56 -58). In fact, a recent study indicated that an in vivo administration of LPS actually reduced myocardial apoptosis induced by I/R injury (48). Moreover, in cell types such as endothelial cells, the induction of LPS-induced apoptosis did not occur unless the production of endogenous survival proteins was blocked (10,11), again suggesting a parallel survival pathways in these cells.…”

Section: Tlr Signaling Modulates Cardiomyocyte Apoptosismentioning

confidence: 97%

“…In animal models of I/R injury (13,18,48,88,89,99,106,138,155,166,167), in both in vivo (13,48,99,138,155,166,167) and ex vivo (18,88,106), a prior systemic administration of a sublethal dose of LPS reduces subsequent MI and improved cardiac functions. For example, hearts isolated from rats pretreated with a low dose of LPS (0.5 mg/kg) 24 h before had a better preserved myocardial function after I/R compared with the saline-treated control hearts (18,105).…”

Section: Lps Preconditioning Against I/r Injurymentioning

confidence: 99%

“…Similar to ischemic preconditioning (16), the cardioprotection conferred by LPS seems to be mediated by iNOS (155) and by Akt (48). Ha and colleagues (48) recently demonstrated that the cardiac benefit of LPS against I/R injury was abolished by an intraperitoneal administration of a PI3-kinase inhibitor or in transgenic mice expressing the inactive Akt mutant. These data suggest that LPS exhibits its cardioprotection via PI3-kinase/ Akt pathway and appear to be consistent with the in vitro observation that Akt, among other survival pathways, mediates a TLR4-mediated antiapoptotic benefit (26,170).…”

Section: Lps Preconditioning Against I/r Injurymentioning

confidence: 99%

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Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

212

166

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Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

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Section: Lps Preconditioning Against I/r Injurymentioning

confidence: 63%

Section: Tlr Signaling Modulates Cardiomyocyte Apoptosismentioning

confidence: 97%

Section: Lps Preconditioning Against I/r Injurymentioning

confidence: 99%

Section: Lps Preconditioning Against I/r Injurymentioning

confidence: 99%

See 2 more Smart Citations

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

212

166

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“…Terminal dUTP nick end-labeling (TUNEL) and caspase-3 activity detection were used to assess apoptosis (21). To examine cardiac myocyte apoptosis, samples of tissue from ischemic zones were fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 5-µm transverse sections.…”

Section: Methodsmentioning

confidence: 99%

Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway

Wang

Zhang

et al. 2013

Braz J Med Biol Res

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Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.

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Grape seed proanthocyanidins protect cardiomyocytes from ischemia and reperfusion injury via Akt‐NOS signaling

Shao

Wojcik

Dossumbekova

et al. 2009

J of Cellular Biochemistry

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Ischemia/reperfusion (I/R) injury in cardiomyocytes is related to excess reactive oxygen species (ROS) generation and can be modulated by nitric oxide (NO). We have previously shown that grape seed proanthocyanidin extract (GSPE), a naturally occurring antioxidant, decreased ROS and may potentially stimulate NO production. In this study, we investigated whether GSPE administration at reperfusion was associated with cardioprotection and enhanced NO production in a cardiomyocyte I/R model. GSPE attenuated I/R-induced cell death [18.0 +/- 1.8% (GSPE, 50 microg/ml) vs. 42.3 +/- 3.0% (I/R control), P < 0.001], restored contractility (6/6 vs. 0/6, respectively), and increased NO release. The NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 200 microM) significantly reduced GSPE-induced NO release and its associated cardioprotection [32.7 +/- 2.7% (GSPE + L-NAME) vs. 18.0 +/- 1.8% (GSPE alone), P < 0.01]. To determine whether GSPE induced NO production was mediated by the Akt-eNOS pathway, we utilized the Akt inhibitor API-2. API-2 (10 microM) abrogated GSPE-induced protection [44.3% +/- 2.2% (GSPE + API-2) vs. 27.0% +/- 4.3% (GSPE alone), P < 0.01], attenuated the enhanced phosphorylation of Akt at Ser473 in GSPE-treated cells and attenuated GSPE-induced NO increases. Simultaneously blocking NOS activation (L-NAME) and Akt (API-2) resulted in decreased NO levels similar to using each inhibitor independently. These data suggest that in the context of GSPE stimulation, Akt may help activate eNOS, leading to protective levels of NO. GSPE offers an alternative approach to therapeutic cardioprotection against I/R injury and may offer unique opportunities to improve cardiovascular health by enhancing NO production and increasing Akt-eNOS signaling.

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Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism

Abstract: These results indicate that LPS-induced cardioprotection in I/R injury is mediated through a PI3K/Akt-dependent mechanism.

Cited by 155 publications

References 37 publications

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway

Grape seed proanthocyanidins protect cardiomyocytes from ischemia and reperfusion injury via Akt‐NOS signaling

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