Thymoquinone attenuates monocrotaline-induced pulmonary artery hypertension via inhibiting pulmonary arterial remodeling in rats

Zhu, Ning; Zhao, Xuyong; Xiang, Yijia; Ye, Shiyong; Huang, Jie; Hu, Wuming; Lv, Linchun; Zeng, Chunlai

doi:10.1016/j.ijcard.2016.06.192

Cited by 28 publications

(32 citation statements)

References 37 publications

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“…MCT induces severe PAH and this animal model imitates certain key characteristics of human PAH, including pulmonary vascular remodeling, PASMC proliferation, and oxidative stress [37], [38]. In this study, our data revealed that 4-HNE levels were significantly elevated in the lungs of rats with MCT-induced PAH and that 4-HNE promoted the proliferation and migration of HPASMCs in vitro .…”

Section: Discussionsupporting

confidence: 55%

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Liu

et al. 2017

Redox Biology

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The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1 μM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.

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Section: Discussionsupporting

confidence: 55%

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Liu

et al. 2017

Redox Biology

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“…The ligation caused the increase in medial thickness and neointimal formation through VSMC proliferation and migration. The dose of 8 mg/kg and 16 mg/kg TQ was chosen according to our previous study, and did not show any signs of toxicity or weight loss during the entire study. As expected, the neointimal formation induced by ligation was reversed by TQ (8 mg/kg and 16 mg/kg) treatment (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…The effects of TQ in cardiovascular diseases have not been well identified. In our previous study, TQ was found to ameliorate monocrotaline‐induced PAH in rats . TQ inhibited small pulmonary arterial remodelling and pulmonary arterial VSMC proliferation in vivo.…”

Section: Introductionmentioning

confidence: 90%

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Thymoquinone suppresses platelet‐derived growth factor‐BB–induced vascular smooth muscle cell proliferation, migration and neointimal formation

Zhu

Xiang

Zhao

et al. 2019

J Cellular Molecular Medi

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The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are mainly responsible for vascular occlusion diseases, such as pulmonary arterial hypertension and restenosis. Our previous study demonstrated thymoquinone (TQ) attenuated monocrotaline‐induced pulmonary arterial hypertension. The aim of the present study is to systematically examine inhibitory effects of TQ on platelet‐derived growth factor‐BB (PDGF‐BB)–induced proliferation and migration of VSMCs in vitro and neointimal formation in vivo and elucidate the potential mechanisms. Vascular smooth muscle cells were isolated from the aorta in rats. Cell viability and proliferation were measured in VSMCs using the MTT assay. Cell migration was detected by wound healing assay and Transwell assay. Alpha‐smooth muscle actin (α‐SMA) and Ki‐67‐positive cells were examined by immunofluorescence staining. Reactive oxygen species (ROS) generation and apoptosis were measured by flow cytometry and terminal deoxyribonucleotide transferase–mediated dUTP nick end labelling (TUNEL) staining, respectively. Molecules including the mitochondria‐dependent apoptosis factors, matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), PTEN/AKT and mitogen‐activated protein kinases (MAPKs) were determined by Western blot. Neointimal formation was induced by ligation in male Sprague Dawley rats and evaluated by HE staining. Thymoquinone inhibited PDGF‐BB–induced VSMC proliferation and the increase in α‐SMA and Ki‐67‐positive cells. Thymoquinone also induced apoptosis via mitochondria‐dependent apoptosis pathway and p38MAPK. Thymoquinone blocked VSMC migration by inhibiting MMP2. Finally, TQ reversed neointimal formation induced by ligation in rats. Thus, TQ is a potential candidate for the prevention and treatment of occlusive vascular diseases.

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“…Rats were randomized into the sham group, model group, thymoquinone pre-treatment group (2.5 mg/kg and 5 mg/kg), and edaravone pre-treatment group (positive control drug, at 3 mg/kg), with 15 rats per group. Thymoquinone was solubilized in olive oil [29] and was administered intraperitoneally at 0.5 mL/100 g body weight qd for 7 days. MCAO surgery was performed 30 min after the final administration.…”

Section: Cerebral Ischemia-reperfusion Modelmentioning

confidence: 99%

Effects of Thymoquinone on Small-Molecule Metabolites in a Rat Model of Cerebral Ischemia Reperfusion Injury Assessed using MALDI-MSI

et al. 2020

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Thymoquinone is one of the main components present in Nigella sativa seeds and is known to have various biological functions in inflammation, oxidative stress, tumors, aging, and in lowering blood glucose levels. Few studies have focused on its neuroprotective effects and its regulation of small-molecule metabolites during cerebral ischemia reperfusion injury. In this study, transient middle cerebral occlusion (tMCAO) was used to establish the rat model of cerebral ischemia reperfusion injury. We investigated the effects of thymoquinone using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) in a model of ischemia reperfusion injury to explore the changes in small-molecule metabolites in the brain. We found that that thymoquinone significantly improved neurobehavioral scores, reduced the cerebral infarct area, alleviated brain edema, and increased the number of normal neurons following injury. MALDI-MSI revealed that thymoquinone reduced abnormal accumulations of glucose, citric acid, succinate and potassium ions. Thymoquinone also increased the amount of energy-related molecules such as ADP, AMP, GMP, and creatine, antioxidants such as glutathione, ascorbic acid, and taurine, and other metabolism-related molecules such as glutamate, glutamine, aspartate, N-acetyl-L-aspartate, and sodium ions in damaged areas of the brain following cerebral ischemia reperfusion injury. In summary, based on the neuroprotective effect of thymoquinone on cerebral ischemia reperfusion injury, this study revealed the regulation of thymoquinone on energy metabolism and small-molecule substance metabolism.

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Thymoquinone attenuates monocrotaline-induced pulmonary artery hypertension via inhibiting pulmonary arterial remodeling in rats

Cited by 28 publications

References 37 publications

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Thymoquinone suppresses platelet‐derived growth factor‐BB–induced vascular smooth muscle cell proliferation, migration and neointimal formation

Effects of Thymoquinone on Small-Molecule Metabolites in a Rat Model of Cerebral Ischemia Reperfusion Injury Assessed using MALDI-MSI

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