Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway

Li, Xiangzhong; Yang, Yue; Geng, Yong–Jian; Jin, Chen; Hu, Feng; Zhao, Jing; Zhang, Hai Tao; Yu, Cheng; Qian, Hai; Wang, Lin Lin; Zhang, Bao Jie; Wu, Yi

doi:10.1152/ajpheart.00459.2010

Cited by 57 publications

(72 citation statements)

References 32 publications

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“…As described previously [4,14] , 6-month-old Chinese Minipigs weighing 20 to 30 kg were anesthetized with a mixture of 700 mg ketamine hydrochloride and 30 mg diazepam administered intramuscularly and were continuously infused with this mixture (2 mg/kg per hour) intravenously to maintain the anesthesia. Minipigs were assigned to 1 of 7 groups (n=7-8 in each group): control, simvastatin (SIM), SIM coadministered with H-89 (SIM+H-89), H-89, SIM coadministered with N ω -nitro-L-arginine (L-NNA; SIM+L-NNA), L-NNA, and sham group.…”

Section: Animal Experimental Protocolsmentioning

confidence: 99%

“…Analysis of myocardial area at risk (AAR), area of no-reflow (ANR), and area of necrosis (AN) Myocardial AAR, ANR, and AN were measured according to previous methods [4,14] . In brief, the area of impaired perfusion was delineated by a bolus of 4% fluorescent thioflavin S (1 mL/kg, Sigma, USA) into the left atrium.…”

Section: Animal Experimental Protocolsmentioning

confidence: 99%

“…Tissue PKA activity assay PKA activity was measured according to the method described previously using a nonradioactive PKA assay kit www.chinaphar.com Li XD et al Acta Pharmacologica Sinica npg (Promega, USA) [14,18] . Tissue samples from NA, AR, and ANR were homogenized on ice in PKA extraction buffer containing 25 mmol/L Tris-HCl (pH 7.4), 0.5 mmol/L EDTA, 0.5 mmol/L EGTA, 10 mmol/L β-mercaptoethanol, 1 μg/mL leupeptin, and 1 μg/mL aprotinin.…”

Section: Animal Experimental Protocolsmentioning

confidence: 99%

“…It is not clinically practical to pre-treat patients undergoing acute post-infarct percutaneous coronary intervention with high-dose statins several days before the procedure. In addition, recent studies have reported that the cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) pathway plays a role in cardioprotection during ischemic preconditioning and in the cardioprotection provided by Tongxinluo, a traditional Chinese medicine [12][13][14] , but it is unclear whether PKA is associated with the cardioprotective effects of statins. Therefore, in this study, we tested the hypothesis that acute pretreatment with singledose statins before reperfusion exerts a cardioprotective effect against myocardial no-reflow and infarction by enhancing eNOS activity in a PKA-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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Aim: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statinmediated eNOS phosphorylation and cardioprotection. Methods: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. Results: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser 133 p-CREB protein, Ser 1179 p-eNOS, and Ser 635 p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg -1 ·min -1 ) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg -1 ) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. Conclusion: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser 1179 and Ser 635 that was partially mediated via the PKA signaling pathway.

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Section: Animal Experimental Protocolsmentioning

confidence: 99%

Section: Animal Experimental Protocolsmentioning

confidence: 99%

Section: Animal Experimental Protocolsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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“…Tongxinluo (TXL) is a compound made from a group of herbal medicines, such as ginseng, radix paeoniae rubra, borneol and spiny jujuba seed, and contains multiple active components that may be responsible for its antianginal effects (Li et al, 2010;Jia et al, 2011;. TXL is then concentrated and freeze-dried before use.…”

Section: Introductionmentioning

confidence: 99%

Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo

Wang

Liu

et al. 2015

Cell Communication & Adhesion

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Activated macrophages contribute to endothelial dysfunction; however, it is unclear how peroxynitrite contributes to macrophage-mediated human cardiac microvascular endothelial cell (HCMEC) injury in hypoxia. In macrophage-HCMEC co-cultures subjected to hypoxia, there was an increase in hypoxia-inducible factor (HIF)-1a, HIF-2a, inducible nitric oxide synthase (iNOS), endothelin-converting enzyme (ECE)-1 and cyclooxygenase-2 (COX-2), and concomitant decrease in prostacyclin synthase (PGIS). This was mimicked by a peroxynitrite donor and attenuated by its decomposition catalyst. Tongxinluo (TXL) could decrease HIF-2a, iNOS, ECE-1 and COX-2 and increase PGIS in a dose-dependent manner, with increase of vascular endothelial growth factor. The protein alterations verified the remarkably affected mRNAs, indicating that the effects of TXL were similar to but better than that of peroxynitrite decomposition catalyst. Furthermore, TXL inhibited macrophage-mediated nitrotyrosine accumulation and attenuated HCMEC injury. The results suggest that peroxynitrite contributes to macrophage-mediated HCMEC injury in hypoxia, and TXL attenuates HCMEC injury mainly by inhibiting peroxynitrite. ARTICLE HISTORY

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Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction

Yang,

Li,

Chen

et al. 2023

JAMA

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ImportanceTongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials.ObjectiveTo investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI).Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021.InterventionsPatients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08 g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments.Main Outcomes and MeasuresThe primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year.ResultsAmong 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], −1.8% [95% CI, −3.2% to −0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, −1.2% [95% CI, −2.5% to −0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, −3.0% [95% CI, −4.6% to −1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, −1.6% [95% CI, −3.1% to −0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (&lt;24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms.Conclusions and RelevanceIn patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI.Trial RegistrationClinicalTrials.gov Identifier: NCT03792035

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Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway

Cited by 57 publications

References 32 publications

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo

Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction

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