Lumbrokinase attenuates myocardial ischemia-reperfusion injury by inhibiting TLR4 signaling

Wang, Yi-Hsin; Chen, Kemin; Chiu, Ping-Sung; Lai, Shih‐Chan; Su, Hsing-Hui; Jan, Ming‐Shiou; Lin, Ching-Yi; Lu, Dah‐Yuu; Fu, Yuan-Tsung; Liao, Jiuan-Miaw; Chang, Jinghua Tsai; Huang, Shiang‐Suo

doi:10.1016/j.yjmcc.2016.08.004

Cited by 33 publications

(31 citation statements)

References 35 publications

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“…The innate immune and inflammatory responses mediated by Toll‐like receptors (TLRs) have been previously demonstrated to play important roles in ischemic injury (Christia & Frangogiannis, ; Prabhu & Frangogiannis, ). Recent studies have indicated that TLRs may be important targets for the development of new treatment approaches for ischemic heart disease (Wang et al, ; Yang et al, ).…”

Section: Introductionmentioning

confidence: 99%

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Zhou

Jiang³

et al. 2017

Journal Cellular Physiology

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Unmethylated CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG-ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG-ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG-ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI. Both 1826-CpG and KSK-CpG preconditioning significantly improved the left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) when compared with non-CpG controls. Histological analysis further confirmed the cardioprotection of CpG-ODN preconditioning. In vitro studies further demonstrated that CpG-ODN preconditioning increases cardiomyocyte survival under hypoxic/ischemic conditions by enhancing stress tolerance through TLR9-mediated inhibition of the SERCA2/ATP and activation of AMPK pathways. Moreover, CpG-ODN preconditioning significantly increased angiogenesis in the infarcted myocardium compared with non-CpG. However, persistent TLR9 activation mediated by lentiviral infection failed to improve cardiac function after MI. Although CpG-ODN preconditioning increased angiogenesis in vitro, both the persistent stimulation of CpG-ODN and stable overexpression of TLR9 suppressed the tube formation of cardiac microvascular endothelial cells. CpG-ODN preconditioning significantly protects cardiac function against MI by suppressing the energy metabolism of cardiomyocytes and promoting angiogenesis. Our data also indicate that CpG-ODN preconditioning may be useful in MI therapy.

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Section: Introductionmentioning

confidence: 99%

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Zhou

Jiang³

et al. 2017

Journal Cellular Physiology

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“…In addition, Taurine was found that it promoted synapse development and proliferation of neuron ( Liu et al, 2010 ). Lumbrokinase may relieve ischemia-reperfusion injury via TLR4 signaling ( Wang et al, 2016 ). In all, It was found that 34 potential compounds in LP were preserved for subsequent analysis.…”

Section: Resultsmentioning

confidence: 99%

Assessing the Pharmacological and Therapeutic Efficacy of Traditional Chinese Medicine Liangxue Tongyu Prescription for Intracerebral Hemorrhagic Stroke in Neurological Disease Models

Huang²,

Tang

et al. 2018

Front. Pharmacol.

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Intracerebral hemorrhage is a fatal subtype of stroke, with crucial impact on public health. Surgical removal of the hematoma as an early-stage treatment for ICH can’t improve long-term prognosis remarkably. Liangxue tongyu prescription (LP), a Traditional Chinese Medicine (TCM) formula, includes eight ingredients and has been used to treat ICH in the clinical. In the study, we elucidated the pharmacological efficacy and therapeutic efficacy of LP to dissect the mechanism of LP against ICH via network analysis and experimental validation. First, we discovered 34 potential compounds and 146 corresponding targets in LP based on network prediction. 24 signal pathway were obtained by the Clue Go assay based on potential compounds in LP against ICH. Second, we found that LP can not only decreased the level of high sensitive C reactive protein (HS-CRP), tumor necrosis factor-α (TNF-α), NF-kβ, D-dimmer (D2D), estradiol (E2), S-100B, neuron specific enolase (NSE), and interleukin 1 (IL-1) in plasma on spontaneously hypertensive rats (SHRs), but also promoted cell proliferation and inhibited cell apoptosis on the glutamate-induced PC12 cell. The compounds including Taurine, Paeonol, and Ginsenoside Rb1 in LP can activate PI3K/AKT pathway. Third, from the three-factor two-level factorial design, compound combinations in LP, such as Taurine and Paeonol, Taurine and Geniposide, Ginsenoside Rg1, and Ginsenoside Rb1, had first-level interactions on cell proliferation. Compound combinations including Taurine and Paeonol, Ginsenoside Rg1 and Ginsenoside Rb1 had as significant increase in efficiency on inhibiting the apoptosis of PC12 cells at the low concentration and up-regulating of PI3K and AKT. Overall, our results suggested that LP had integrated therapeutic effect on ICH due to activities of anti-inflammatory, anti-coagulation, blood vessel protection, and protection neuron from excitotoxicity based on the way of “multi-component, multi-target, multi-pathway,” and compound combination in LP can offer protection neuron from excitotoxicity at the low concentration by activation of the PI3K/Akt signal pathway.

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“…Thus, lumbrokinase is not associated with the excessive bleeding and heavy blood loss seen with streptokinase or urokinase, which may result in death ( Delaney et al, 2007 ; Vernooij et al, 2009 ). In our previous study, pre-treatment with lumbrokinase 10 μg/kg significantly reduced ventricular arrhythmias and myocardial infarction in rats after myocardial I-R injury ( Wang et al, 2016 ). We suggested that lumbrokinase has significant potential as a cardioprotective agent, regulating anti-inflammatory mechanisms that protect the heart against I-R injury ( Wang et al, 2016 ).…”

Section: Introductionmentioning

confidence: 89%

“…In our previous study, pre-treatment with lumbrokinase 10 μg/kg significantly reduced ventricular arrhythmias and myocardial infarction in rats after myocardial I-R injury ( Wang et al, 2016 ). We suggested that lumbrokinase has significant potential as a cardioprotective agent, regulating anti-inflammatory mechanisms that protect the heart against I-R injury ( Wang et al, 2016 ). Oral lumbrokinase supplementation has been used in Japan, Korea, Canada and the United States to support and maintain healthy cardiovascular function.…”

Section: Introductionmentioning

confidence: 89%

“…Myocardial I-R injury was induced by temporary occlusion of the left anterior descending coronary artery, according to a previously described procedure ( Wang et al, 2016 ). Slight modification of the procedure meant that the left anterior descending coronary artery was occluded by tightening of the ligature to induce ischemia for 30 min, followed by 3 h of reperfusion.…”

Section: Methodsmentioning

confidence: 99%

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Sirt1 Activation by Post-ischemic Treatment With Lumbrokinase Protects Against Myocardial Ischemia-Reperfusion Injury

Wang

Huang³

et al. 2018

Front. Pharmacol.

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Lumbrokinase is used as an oral supplement to support and maintain healthy cardiovascular function, and to treat cardiovascular diseases in clinical for more than 10 years. Up until now, the mechanism of the cardioprotective effects of post-ischemic treatment with lumbrokinase has remained unclear. We therefore investigated the signaling pathways involved in the amelioration of myocardial ischemia-reperfusion (I-R) injury in rats treated with lumbrokinase 20 min after myocardial ischemia. Compared to vehicle-treated rats, post-ischemic treatment with lumbrokinase was associated with significant reductions in myocardial I-R-induced arrhythmias and myocardial damage, and an improvement in cardiac function. Moreover, lumbrokinase significantly upregulated levels of silent information regulator 1 (Sirt1). In addition, lumbrokinase significantly increased manganese-dependent superoxide dismutase expression, decreased Cleaved-Caspase-3 expression, and induced deacetylation of FoxO1. On the other hand, lumbrokinase also significantly downregulated levels of succinate dehydrogenase, cytochrome c oxidase, nuclear factor kappa B (NF-κB) and elevated levels of microtubule-associated protein light chain 3. Notably, the cardioprotective effects of lumbrokinase were abolished by administration of the specific Sirt1 inhibitor EX527. These findings demonstrate that post-ischemic treatment with lumbrokinase attenuates myocardial I-R injury through the activation of Sirt1 signaling, and thus enhances autophagic flux and reduces I-R-induced oxidative damage, inflammation and apoptosis.

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Lumbrokinase attenuates myocardial ischemia-reperfusion injury by inhibiting TLR4 signaling

Cited by 33 publications

References 35 publications

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis

Assessing the Pharmacological and Therapeutic Efficacy of Traditional Chinese Medicine Liangxue Tongyu Prescription for Intracerebral Hemorrhagic Stroke in Neurological Disease Models

Sirt1 Activation by Post-ischemic Treatment With Lumbrokinase Protects Against Myocardial Ischemia-Reperfusion Injury

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