A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice

Ma, Zhen‐Guo; Zhang, Xin; Yao, Yuan; Jin, Ya‐Ge; Li, Ning; Kong, Chun-Yan; Song, Peng

doi:10.1042/cs20180160

Cited by 37 publications

(28 citation statements)

References 56 publications

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“…Transthoracic echocardiography was performed according to our previous studies, and echocardiographic parameters were averaged from three to five cardiac cycles [33][34][35][36][37]. Particular attention was given not to bring excessive pressure to the chest, which could cause bradycardia and deformation of the heart.…”

Section: Echocardiography and Hemodynamicsmentioning

confidence: 99%

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FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

et al. 2019

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Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.

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Section: Echocardiography and Hemodynamicsmentioning

confidence: 99%

“…Western blot and quantitative real-time PCR were performed referring to our previous articles [33][34][35][36][37]. Nuclear protein fractions were separated by a commercial kit as our previously described and were normalized to PCNA [9,33].…”

Section: Western Blot and Quantitative Real-time Pcrmentioning

confidence: 99%

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

et al. 2019

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“…Undoubtedly, cardiac hypertrophy plays an important role in the occurrence and development of HF. Pharmacological inhibition of cardiac hypertrophy may be a good way to prevent and treat HF …”

Section: Introductionmentioning

confidence: 99%

Cordycepin ameliorates cardiac hypertrophy via activating the AMPKα pathway

Wang

Duan

et al. 2019

J Cellular Molecular Medi

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Increase of myocardial oxidative stress is closely related to the occurrence and development of cardiac hypertrophy. Cordycepin, also known as 3'‐deoxyadenosine, is a natural bioactive substance extracted from Cordyceps militaris (which is widely cultivated for commercial use in functional foods and medicine). Since cordycepin suppresses oxidative stress both in vitro and in vivo, we hypothesized that cordycepin would inhibit cardiac hypertrophy by blocking oxidative stress‐dependent related signalling. In our study, a mouse model of cardiac hypertrophy was induced by aortic banding (AB) surgery. Mice were intraperitoneally injected with cordycepin (20 mg/kg/d) or the same volume of vehicle 3 days after‐surgery for 4 weeks. Our data demonstrated that cordycepin prevented cardiac hypertrophy induced by AB, as assessed by haemodynamic parameters analysis and echocardiographic, histological and molecular analyses. Oxidative stress was estimated by detecting superoxide generation, superoxide dismutase (SOD) activity and malondialdehyde levels, and by detecting the protein levels of gp91 phox and SOD. Mechanistically, we found that cordycepin activated activated protein kinase α (AMPKα) signalling and attenuated oxidative stress both in vivo in cordycepin‐treated mice and in vitro in cordycepin treated cardiomyocytes. Taken together, the results suggest that cordycepin protects against post‐AB cardiac hypertrophy through activation of the AMPKα pathway, which subsequently attenuates oxidative stress.

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“…Лефлуномид способен ингибировать NFκB сигнальные пути, снижать субэндотелиальную миграцию периферических мононуклеарных клеток крови и вызывать функциональные нарушения антиген-презентирующих дендритных клеток [23]. Лефлуномид ингибирует агрегацию тромбоцитов in vitro [24] и предотвращает гипертрофию и фиброз миокарда in vivo и in vitro через подавление активации Akt (протеин киназы B) сигнального пути [25]. Использование лефлуномида при РА ассоциируется со снижением вероятности ИМ [26,27], однако риск выше, чем при лечении метотрексатом [28].…”

Section: лефлуномидunclassified

Chronic Heart Failure in Rheumatoid Arthritis Patients (Part III): Effects of Antirheumatic Drugs

Новикова¹,

Udachkina²,

Kirillova³

et al. 2020

Racionalʹnaâ farmakoterapiâ v kardiologii

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Chronic autoimmune inflammation is one of the leading risk factors for the development of chronic heart failure (CHF) in rheumatoid arthritis (RA). The purpose of the review is to analyze the results of investigations on the effects of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological disease-modifying anti-rheumatic drugs (bDMARDs), and targeted csDMARDs on cardiac function and the risk of developing CHF in patients with RA. Methotrexate may reduce the CHF risk and have a positive effect on the course of this condition in patients with RA. Despite the data on the presence of leflunomide effects that impede myocardial remodeling, there is no evidence of the role of the drug in the prevention of CHF in RA patients. Hydroxychloroquine may contribute to the prevention of CHF, but the risk of developing severe cardiotoxicity should be considered when taking the drug for a long time. Most studies have not revealed the negative effect of tumor necrosis factor inhibitors on the prevalence and incidence of new cases of CHF in RA patients, and an improvement in the structure and function of the heart during therapy has been shown. Inhibitors of interleukin (IL) -1, inhibitors of IL-6, inhibitors of T-cell co-stimulation, anti-B-cell therapy, targeted csDMARDs do not increase the risk of CHF and may have cardioprotective effects, including slowing the progression of left ventricle myocardial dysfunction. Due to the high risk of CHF and CHF-associated mortality in RA patients, early diagnosis of cardiac dysfunction, development of a prevention and treatment strategies are needed, including high-quality prospective studies to assess the effect of anti-rheumatic therapy on myocardial function, risk of developing and decompensation of CHF in RA patients. It is possible that some drugs may possess protective effects on cardiomyocytes so they could become the first-line drugs in patients with CHF or the risk of its development.

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A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice

Cited by 37 publications

References 56 publications

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

Cordycepin ameliorates cardiac hypertrophy via activating the AMPKα pathway

Chronic Heart Failure in Rheumatoid Arthritis Patients (Part III): Effects of Antirheumatic Drugs

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