Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis

Li, Fuhai; Wang, Jingfeng; Song, Yu; Shen, Dongli; Zhao, Yongchao; Li, Chaofu; Fu, Mingqiang; Wang, Yanyan; Qi, Baozheng; Han, Xueting; Sun, Aijun; Zhou, Jingmin; Ge, Junbo

doi:10.1016/j.lfs.2021.119239

Cited by 11 publications

(8 citation statements)

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“…CMECs were cultured as previously described. [28][29][30][31] Briefly, 2-week-old male standard deviation (SD) rats were cervical dislocated, and the hearts were removed. Next, the epicardial and endocardial tissues were removed by ophthalmic forceps, the ventricular tissues were split into 1 mm 3 , plated in dishes pre-coated with 1 mL FBS (BI, #04-001-1A), and cultured for 4 h. Then high-glucose DMEC (Gibco, #1791920) with 10% FBS was added for another 48 h of incubation.…”

Section: Cmecs Isolation and Treatmentmentioning

confidence: 99%

Loss of m6A demethylase ALKBH5 promotes post‐ischemic angiogenesis via post‐transcriptional stabilization of WNT5A

Zhao

Sun

et al. 2021

Clinical & Translational Med

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Background: Post-ischemic angiogenesis is critical for blood flow recovery and ischemic tissue repair. N6-methyladenosine (m6A) plays essential roles in numerous biological processes. However, the impact and connected mechanism of m6A on post-ischemic angiogenesis are not fully understood. Methods: AlkB homolog 5 (ALKBH5) was screened out among several methyltransferases and demethylases involved in dynamic m6A regulation. Cardiac microvascular endothelial cells (CMECs) angiogenesis and WNT family member 5A (WNT5A) stability were analyzed upon ALKBH5 overexpression with adenovirus or knockdown with small interfering RNAs in vitro. The blood flow recovery, capillary, and small artery densities were evaluated in adeno-associated virus (AAV)-ALKBH5 overexpression or ALKBH5 knockout (KO) mice in a hind-limb ischemia model. The same experiments were conducted to explore the translational value of transient silencing of ALKBH5 with adenovirus. Results: ALKBH5 was significantly upregulated in hypoxic CMECs and led to a global decrease of m6A level. ALKBH5 overexpression further reduced m6A level in normoxic and hypoxic CMECs, impaired proliferation, migration, and tube formation only in hypoxic CMECs. Conversely, ALKBH5 knockdown preserved m6A levels and promoted angiogenic phenotypes in hypoxic but not in normoxic CMECs. Mechanistically, ALKBH5 regulated WNT5A expression through post-transcriptional mRNA modulation in an m6A-dependent manner, which decreased its stability and subsequently impeded angiogenesis in hypoxic CMECs. Furthermore, ALKBH5 overexpression hindered blood flow

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Section: Cmecs Isolation and Treatmentmentioning

confidence: 99%

Loss of m6A demethylase ALKBH5 promotes post‐ischemic angiogenesis via post‐transcriptional stabilization of WNT5A

Zhao

Sun

et al. 2021

Clinical & Translational Med

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“…Studies by the group led by Ge et al [91][92][93][94][95][96][97][98][99] highlighted a role of enhanced Akt/mTOR/HIF-1α/NRG-1/Erbb2 signalling in mediating QXQL cardioprotection during acute marked injury (Figure 4). In hypoxic cardiac microvascular endothelial cells, QLQX alleviated oxidative stress, mitochondrial dysfunction and apoptosis; these benefits were accompanied by upregulation of Akt/mTOR/HIF-1α/NRG-1 signalling and downregulation of AMPK and were abolished by HIF-1α, NRG-1 and Akt silencing and by AMPK activation.…”

Section: Mechanistic Studies Of Qiliqiangxin In Marked Abrupt Cardiac...mentioning

confidence: 99%

Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

Packer

2023

European J of Heart Fail

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The active ingredients in many traditional Chinese medicines are isoprene oligomers with a diterpenoid or triterpenoid structure, which exert cardiovascular effects by signaling through nutrient surplus and nutrient deprivation pathways. Qiliqiangxin (QLQX) is a commercial formulation of 11 different plant ingredients, whose active compounds include astragaloside IV, tanshione IIA, ginsenosides (Rb1, Rg1 and Re) and periplocymarin. In the QUEST Trial, QLQX reduced the combined risk of cardiovascular death or heart failure hospitalization (hazard ratio 0.78 [95% CI 0.68‐0.90]), based on 859 events in 3119 patients over a median of 18.2 months; the benefits were seen in patients taking foundational drugs except for SGLT2 inhibitors. Numerous experimental studies of QLQX in diverse cardiac injuries have yielded highly consistent findings. In marked abrupt cardiac injury, QLQX mitigated cardiac injury by upregulating nutrient surplus signaling through the PI3K/Akt/mTOR/HIF‐1α/NRF2 pathway; the benefits of QLQX were abrogated by suppression of PI3K, Akt, mTOR, HIF‐1α or NRF2. In contrast, in prolonged measured cardiac stress (as in chronic heart failure), QLQX ameliorated oxidative stress, maladaptive hypertrophy, cardiomyocyte apoptosis, and proinflammatory and profibrotic pathways, while enhancing mitochondrial health and promoting glucose and fatty acid oxidation and ATP production. These effects are achieved by an action of QLQX to upregulate nutrient deprivation signaling through SIRT1/AMPK/PGC‐1α and enhanced autophagic flux. In particular, QLQX appears to enhance the interaction of PGC‐1α with PPARα, possibly by direct binding to RXRα; silencing of SIRT1, PGC‐1α and RXRα abrogated the favorable effects of QLQX in the heart. Since PGC‐1α/RXRα is also a downstream effector of Akt/mTOR signaling, the actions of QLQX on PGC‐1α/RXRα may explain its favorable effects in both acute and chronic stress. Intriguingly, the individual ingredients in QLQX — astragaloside IV, ginsenosides, and tanshione IIA — share QLQX's effects on PGC‐1α/RXRα/PPARα signaling. QXQL also contains periplocymarin, a cardiac glycoside that inhibits Na+‐K+‐ATPase. Taken collectively, these observations support a conceptual framework for understanding the mechanism of action for QLQX in heart failure. The high likelihood of overlap in the mechanism of action of QLQX and SGLT2 inhibitors requires additional experimental studies and clinical trials.This article is protected by copyright. All rights reserved.

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“…QLQX can improve the heart function of HF rats and increase the excretion of water by reducing the expression of AQP2 in the kidneys ( Cui et al, 2015 ). It can also reduce the expression of Ang II and periostin protein in HF rats after myocardial infarction ( Zhou et al, 2015 ; Li F. et al, 2021 ), while the immunomodulatory effects of anti-inflammatory factors might be one of the immunopharmacological mechanisms of QLQX to improve the heart function of AMI rats. These previous cells and animal studies regarding the effect of QLQX in various models have shown the protective effects on inhibiting pathological cardiac remodeling, mechanistically via activation of PPARγ ( He et al, 2013 ; Pan et al, 2014 ; Wang H. et al, 2017 ), and the protective effect of QLQX in the heart might also be attributed, but not limited, to the blood glucose reduction effect ( Wu et al, 2021 ).…”

Section: Translation In Modern Medicinementioning

confidence: 99%

Integrating Evidence of the Traditional Chinese Medicine Collateral Disease Theory in Prevention and Treatment of Cardiovascular Continuum

et al. 2022

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Cardiovascular disease has become a major public health problem. The concept of “cardiovascular continuum” refers to the continuous process from the risk factors that lead to arteriosclerosis, vulnerable plaque rupture, myocardial infarction, arrhythmia, heart failure, and death. These characteristics of etiology and progressive development coincide with the idea of “preventing disease” in traditional Chinese medicine (TCM), which corresponds to the process of systemic intervention. With the update of the understanding via translational medicine, this article reviews the current evidence of the TCM collateral disease theory set prescriptions in both mechanical and clinical aspects, which could lead to the development of new therapeutic strategies for prevention and treatment.

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Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis

Cited by 11 publications

References 53 publications

Loss of m6A demethylase ALKBH5 promotes post‐ischemic angiogenesis via post‐transcriptional stabilization of WNT5A

Loss of m6A demethylase ALKBH5 promotes post‐ischemic angiogenesis via post‐transcriptional stabilization of WNT5A

Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

Integrating Evidence of the Traditional Chinese Medicine Collateral Disease Theory in Prevention and Treatment of Cardiovascular Continuum

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