Tongxinluo attenuates reperfusion injury in diabetic hearts by angiopoietin-like 4-mediated protection of endothelial barrier integrity via PPAR-α pathway

Kang, Qi; Li, Xiangdong; Geng, Yong–Jian; Cui, Hehe; Jin, Chen; Wang, Peihe; Li, Yue; Yang, Yuejin

doi:10.1371/journal.pone.0198403

Cited by 21 publications

(25 citation statements)

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“…ANGPTL4 is the target of peroxisome proliferator-activated receptors (PPAR) and induced by PPARα in mice and rat models [ 16 , 17 , 18 ]. Muscle-derived ANGPTL4 is induced by fatty acids via PPARδ, but not PPARα, and PPARγ in human skeletal muscle myotubes [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Skeletal Muscle Angiopoietin-Like Protein 4 and Glucose Metabolism in Older Adults after Exercise and Weight Loss

Zhang

Ryan

2020

Metabolites

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Angiopoietin-like protein 4 (ANGPTL4) is an adipokine that plays an important role in energy homoeostasis and lipid and lipoprotein metabolism. This study was designed to determine the effect of an exercise plus weight loss intervention on ANGPTL4 expression and its relationship with metabolic health. Thirty-five obese sedentary men (n = 18) and postmenopausal women (n = 17), (X ± SEM, age: 61 ± 1 years, BMI: 31.3 ± 0.7 kg/m2, VO2max: 21.7 ± 0.9 L/kg/min) completed a 6 month program of 3×/week aerobic exercise and 1×/week dietary instruction to induce weight loss (AEX + WL). Participants underwent vastus lateralis muscle biopsies, a hyperinsulinemic–euglycemic clamp, oral glucose tolerance tests and body composition testing. Basal skeletal muscle ANGPTL4 mRNA was lower in men than women (p < 0.01). Peroxisome proliferator-activated receptor (PPAR) alpha (PPARα) mRNA expression was higher in men than women (p < 0.05). There were no significance changes in serum or skeletal muscle ANGPTL4 (basal or insulin-stimulated) or muscle PPARα mRNA expression after AEX + WL. Muscle mRNA ANGPTL4 is correlated with serum ANGPTL4 (r = 0.41, p < 0.05), body fat (r = 0.64, p < 0.0001), and glucose utilization (r = 0.38, p < 0.05). AEX + WL does not change basal or insulin-stimulated skeletal muscle ANGPTL4 mRNA expression, suggesting other factors contribute to improved insulin sensitivity after the loss of body fat and improved fitness.

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Section: Introductionmentioning

confidence: 99%

Skeletal Muscle Angiopoietin-Like Protein 4 and Glucose Metabolism in Older Adults after Exercise and Weight Loss

Zhang

Ryan

2020

Metabolites

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“…Composed of Radix ginseng, Buthus martensi, Hirudo, Eupolyphaga seu steleophaga, Scolopendra subspinipes, Periostracum cicadae, Radix paeoniae rubra, Semen ziziphi spinosae, Lignum dalbergiae odoriferae, Lignum santali albi, and Borneolum syntheticum, traditional Chinese medicine Tongxinluo (TXL) was registered in China Food and Drug Administration for the angina pectoris treatment in 1996. Recent researches demonstrated that TXL could protect the myocardium from I/R-injury, reducing the size of myocardial necrosis and no-reflow, and improving the cardiac performance in both non-diabetic [ 7 ] and diabetic [ 8 ] conditions.…”

Section: Introductionmentioning

confidence: 99%

“…The protection mechanisms of TXL involved the protection of microvascular endothelial integrity by upregulating VE-cadherin, β-catenin, γ-catenin, JAM-A and integrin-α5 and subsequent reduction of myocardial hemorrhage, inflammation, oxidization, edema, apoptosis and necrosis, while eNOS inhibitor Nω-Nitro-L-arginine, peroxisome proliferator activated receptor-α (PPAR-α) inhibitor MK886 or small interfering RNA (siRNA) against angiopoietin-like 4 (Angptl4) partly canceled these effects of TXL, indicating that endothelial barrier function and PPAR-α/Angptl4 pathway played a key role in the protection of TXL against myocardial I/R-injury. [ 7 – 11 ] Several signaling pathways have been implicated in this protective role of TXL, including PKA/eNOS, [ 7 ] MEK/ERK, [ 12 ] and PPAR-α/Angptl4 [ 8 ] pathways.…”

Section: Introductionmentioning

confidence: 99%

“…[ 13 ] Recently, we confirmed that as a key protector, Angptl4 mediated the protection of TXL by regulating endothelial barrier against myocardial I/R-injury in diabetic rats. [ 8 ] However, the relative contribution of cell-intrinsic and endothelial-specific versus circulating Angptl4 from other sources in response to I/R is not yet clear.…”

Section: Introductionmentioning

confidence: 99%

“…Rich in myocardium, PPAR-α activates Angptl4 expression under stresses. [ 14 , 15 ] Noticeably, as a core mechanism, PPAR-α, which could be activated by TXL to protect diabetic rats from myocardial I/R-injury, [ 8 ] is also an important regulator of renal microvascular endothelial barrier. [ 16 ] PPAR-α/Angptl4 pathway is thought to be a protective signaling pathway during I/R in diabetic hearts.…”

Section: Introductionmentioning

confidence: 99%

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Tongxinluo attenuates oxygen-glucose-serum deprivation/restoration-induced endothelial barrier breakdown via peroxisome proliferator activated receptor-α/angiopoietin-like 4 pathway in high glucose-incubated human cardiac microvascular endothelial cells

et al. 2020

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Background: Traditional Chinese medicine Tongxinluo (TXL) has been widely used to treat coronary artery disease in China, since it could reduce myocardial infarct size and ischemia/reperfusion injury in both non-diabetic and diabetic conditions. It has been shown that TXL could regulate peroxisome proliferator activated receptor-α (PPAR-α), a positive modulator of angiopoietin-like 4 (Angptl4), in diabetic rats. Endothelial junction substructure components, such as VE-cadherin, are involved in the protection of reperfusion injury. Thus, we hypothesized cell-intrinsic and endothelial-specific Angptl4 mediated the protection of TXL on endothelial barrier under high glucose condition against ischemia/reperfusion-injury via PPAR-α pathway. Methods: Incubated with high glucose medium, the human cardiac microvascular endothelial cells (HCMECs) were then exposed to oxygen-glucose-serum deprivation (2 hours) and restoration (2 hours) stimulation, with or without TXL, insulin, or rhAngptl4 pretreatment. Results: TXL, insulin, and rhAngptl4 had similar protective effects on the endothelial barrier. TXL treatment reversed the endothelial barrier breakdown in HCMECs significantly as identified by decreasing endothelial permeability, upregulating the expression of JAM-A, VE-cadherin, and integrin-α5 and increasing the membrane location of VE-cadherin and integrin-α5, and these effects of TXL were as effective as insulin and rhAngptl4. However, Angptl4 knock-down with small interfering RNA (siRNA) interference and PPAR-α inhibitor MK886 partially abrogated these beneficial effects of TXL. Western blotting also revealed that similar with insulin, TXL upregulated the expression of Angptl4 in HCMECs, which could be inhibited by Angptl4 siRNA or MK886 exposure. TXL treatment increased PPAR-α activity, which could be diminished by MK886 but not by Angptl4 siRNA. Conclusion: These data suggest cell-intrinsic and endothelial-specific Angptl4 mediates the protection of TXL against endothelial barrier breakdown during oxygen-glucose-serum deprivation and restoration under high glucose condition partly via the PPAR-α/Angptl4 pathway.

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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 attenuates reperfusion injury in diabetic hearts by angiopoietin-like 4-mediated protection of endothelial barrier integrity via PPAR-α pathway

Cited by 21 publications

References 46 publications

Skeletal Muscle Angiopoietin-Like Protein 4 and Glucose Metabolism in Older Adults after Exercise and Weight Loss

Skeletal Muscle Angiopoietin-Like Protein 4 and Glucose Metabolism in Older Adults after Exercise and Weight Loss

Tongxinluo attenuates oxygen-glucose-serum deprivation/restoration-induced endothelial barrier breakdown via peroxisome proliferator activated receptor-α/angiopoietin-like 4 pathway in high glucose-incubated human cardiac microvascular endothelial cells

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

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