NF-κB pathway activation during endothelial-to-mesenchymal transition in a rat model of doxorubicin-induced cardiotoxicity

Xu, Anji; Deng, Fei‐Yan; Chen, Yongyi; Kong, Yu; Pan, Lijun; Liao, Qianjin; Rao, Zhi-Ren; Xie, Luyuan; Yao, Chao‐Ling; Li, Sha; Zeng, Xiaoling; Zhu, Xiaomei; Liu, Huayun; Gao, Nana; Xue, Lei; Chen, Fen; Di, Wei; Zhou, Xiao Yan; Li, Zan; Sheng, Xiaowu

doi:10.1016/j.biopha.2020.110525

Cited by 29 publications

(13 citation statements)

References 54 publications

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“…It is known that chemotherapy with Doxo can induce dose-dependent endothelial dysfunction due to the reduction of vasodilators bioavailability—in particular, nitric oxide—in parallel with increasing the vasoconstrictor agents [ 70 ]. In this process, NF-kB plays an important role as the transcription factor involved in cell proliferation, inflammation and differentiation as a response to oxidative stress [ 71 ]. Generally, free radicals generated by Doxo administration determine the NF-kB translocation into the nucleus and upregulation of different pathways [ 72 ].…”

Section: Resultsmentioning

confidence: 99%

“…Generally, free radicals generated by Doxo administration determine the NF-kB translocation into the nucleus and upregulation of different pathways [ 72 ]. El-Agamy et al [ 73 ] demonstrated that Nrf2 and NF-kB inhibition by Pristimerin reduced the cardiotoxicity triggered by Doxo, while Xu et al [ 71 ] found high expressions of p53 and phosphorylated p53 in Doxo heart rat vessels compared to untreated vessels. These findings confirmed the translocation of p53 into the nucleus after a Doxo treatment and NF-kB pathway activation and, also, its involvement in cardiac fibrosis [ 74 ].…”

Section: Resultsmentioning

confidence: 99%

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Comparative Study of the Pharmacological Properties and Biological Effects of Polygonum aviculare L. herba Extract-Entrapped Liposomes versus Quercetin-Entrapped Liposomes on Doxorubicin-Induced Toxicity on HUVECs

et al. 2021

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This study aimed to evaluate the comparative biological effects of Polygonum aviculare L. herba (PAH) extract and quercetin-entrapped liposomes on doxorubicin (Doxo)-induced toxicity in HUVECs. HUVECs were treated with two formulations of liposomes loaded with PAH extract (L5 and L6) and two formulations of liposomes loaded with quercetin (L3 prepared with phosphatidylcholine and L4 prepared with phosphatidylserine). The results obtained with atomic force microscopy, zeta potential and entrapment liposome efficiency confirmed the interactions of the liposomes with PAH or free quercetin and a controlled release of flavonoids entrapped in all the liposomes. Doxo decreased the cell viability and induced oxidative stress, inflammation, DNA lesions and apoptosis in parallel with the activation of Nrf2 and NF-kB. Free quercetin, L3 and L4 inhibited the oxidative stress and inflammation and reduced apoptosis, particularly L3. Additionally, these compounds diminished the Nrf2 and NF-kB expressions and DNA lesions, principally L4. PAH extract, L5 and L6 exerted antioxidant and anti-inflammatory activities, reduced γH2AX formation and inhibited extrinsic apoptosis and transcription factors activation but to a lesser extent. The loading of quercetin in liposomes increased the cell viability and exerted better endothelial protection compared to free quercetin, especially L3. The liposomes with PAH extract had moderate efficiency, mainly due to the antioxidant and anti-inflammatory effects and the inhibition of extrinsic apoptosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Comparative Study of the Pharmacological Properties and Biological Effects of Polygonum aviculare L. herba Extract-Entrapped Liposomes versus Quercetin-Entrapped Liposomes on Doxorubicin-Induced Toxicity on HUVECs

et al. 2021

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“…The process of heart remodeling during HF often involves the activation of several ECs and mesenchymal cell transition-related pathways. These pathways include the cell-cell junction reconstruction [38], increased nuclear factor-κB (NF-κB) transcription factor activity [39], activation of the transforming growth factor β (TGF-β)/fibroblast growth factor (FGF) axis coordinating the endothelial cell plasticity and smooth muscle cell migration motility [40], activation of the Smad2/3-Snail signaling pathway to increase EndMT protein expression [41], and the regulation of microRNA (miRNA) expression for a positive or negative mediation of HF progression [42]. Our results showed that hypertensive or ischemic HF significantly reduced the E-cadherin and VE-cadherin expression and increased vimentin and fibronectin expression in the human and rat HF endocardium.…”

Section: Discussionmentioning

confidence: 99%

Endocardial Endothelial Dysfunction and Unknown Polymorphic Composite Accumulation in Heart Failure

Kuo

Liu

et al. 2021

Biomedicines

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The accumulation of unknown polymorphic composites in the endocardium damages the endocardial endothelium (EE). However, the composition and role of unknown polymorphic composites in heart failure (HF) progression remain unclear. Here, we aimed to explore composite deposition during endocardium damage and HF progression. Adult male Sprague–Dawley rats were divided into two HF groups—angiotensin II-induced HF and left anterior descending artery ligation-induced HF. Heart tissues from patients who had undergone coronary artery bypass graft surgery (non-HF) and those with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) were collected. EE damage, polymorphic unknown composite accumulation, and elements in deposits were examined. HF progression reduced the expression of CD31 in the endocardium, impaired endocardial integrity, and exposed the myofibrils and mitochondria. The damaged endocardial surface showed the accumulation of unknown polymorphic composites. In the animal HF model, especially HF caused by myocardial infarction, the weight and atomic percentages of O, Na, and N in the deposited composites were significantly higher than those of the other groups. The deposited composites in the human HF heart section (DCM) had a significantly higher percentage of Na and S than the other groups, whereas the percentage of C and Na in the DCM and ICM groups was significantly higher than those of the control group. HF causes widespread EE dysfunction, and EndMT was accompanied by polymorphic composites of different shapes and elemental compositions, which further damage and deteriorate heart function.

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“…Although the use of this drug has shown excellent results in the treatment of malignant tumors, but its wider use is hindered by its potential cardiotoxicity, which is clinically manifested by cardiomyopathy and congestive heart failure [15,20,25].…”

Section: Discussionmentioning

confidence: 99%

Dynamics of morphological changes in the heart of rats after serial systemic administration of Doxorubicin

Kostiuk

Hodovan

Gormash³

et al. 2020

Rep. of Morph.

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Along with a good antitumor effect, Doxorubicin has a systemic effect with damage to vital organs, in particular the heart. The lack of a unified approach to dosing and the frequency of administration of Doxorubicin in the experiment prompts the search for an optimal model of Doxorubicin cardiomyopathy. The aim of the study was to develop a method of serial administration of Doxorubicin in medium therapeutic doses in an experiment and to evaluate the cardiotoxic effect of the drug. 42 female Wistar rats were included in the study. The control group consisted of 7 intact rats. The experimental group consisted of 35 rats who received systemic chemotherapy with Doxorubicin at a dose of 5 mg/kg once a week for 5 weeks. On days 7th, 14th, 21st, 28th, 35th, the hearts of experimental animals were taken for morphological examination. Histomorphometrically determined: the diameter of cardiomyocytes (in the middle part) and the transverse diameter of their nucleus, the width of the interstitial space (endo- and perimysia). The data of histomorphological and histomorphometric examination of the myocardium testified that all animals of the experimental group had a circulatory disorder in the heart muscle at the level of hemomicrocirculation. Such changes led to cardiomyocyte hypotrophy, interstitial edema and fibrosis. During systemic chemotherapy, the animals showed marked changes in the myocardium, such as expansion of the endomysial zone, due to capillary congestion and edema, in comparison with animals of the intact group. At the end of the experiment, the animals of the experimental group retained the expansion of the endomysial zone, mainly due to interstitial fibrosis. Such changes indicate myocardial hypoxemia with damage and death of cardiomyocytes, activation of interstitial and replacement collagen formation. The obtained morphological data indicate the development of dilated cardiomyopathy in experimental animals. Serial intraperitoneal administration of Doxorubicin at a dose of 5 mg/kg once a week for 5 weeks causes morphological changes in the myocardium of experimental animals, similar to changes in the heart of people undergoing chemotherapy with this drug.

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NF-κB pathway activation during endothelial-to-mesenchymal transition in a rat model of doxorubicin-induced cardiotoxicity

Cited by 29 publications

References 54 publications

Comparative Study of the Pharmacological Properties and Biological Effects of Polygonum aviculare L. herba Extract-Entrapped Liposomes versus Quercetin-Entrapped Liposomes on Doxorubicin-Induced Toxicity on HUVECs

Comparative Study of the Pharmacological Properties and Biological Effects of Polygonum aviculare L. herba Extract-Entrapped Liposomes versus Quercetin-Entrapped Liposomes on Doxorubicin-Induced Toxicity on HUVECs

Endocardial Endothelial Dysfunction and Unknown Polymorphic Composite Accumulation in Heart Failure

Dynamics of morphological changes in the heart of rats after serial systemic administration of Doxorubicin

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