Inhibition of Src activation reverses pulmonary vascular remodeling in experimental pulmonary arterial hypertension via Akt/mTOR/HIF-1&lt;alpha&gt; signaling pathway

Liu, Pengfei; Gu, Yue; Luo, Jie; Ye, Peng; Zheng, Yaguo; Yu, Wande; Chen, Shao‐Liang

doi:10.1016/j.yexcr.2019.02.022

Cited by 39 publications

(33 citation statements)

References 35 publications

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“…The Src tyrosine kinase family is known to contribute to the proliferation of cancer cells and contribute to vascular remodeling seen in PAH. Inhibition of Src family tyrosine kinases has also been shown to attenuate mitogenic responses to growth factors in PASMCs and pulmonary vascular remodeling in vivo [38,39]. The present study demonstrated the usefulness of targeting Src family tyrosine kinases by EPA and RvE1 for attenuating the enhanced proliferation of IPAH-PASMCs.…”

Section: Discussionsupporting

confidence: 57%

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn

Kurahara

Hiraishi

Yamamura

et al. 2020

Journal of Molecular and Cellular Cardiology

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Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominantnegative Fyn prevented TGF-β2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.

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Section: Discussionsupporting

confidence: 57%

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn

Kurahara

Hiraishi

Yamamura

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…Src kinases have been suggested to be involved in the exacerbation of neurodegenerative pathologies, whereas their inhibition would diminish microgliosis and mitigate inflammation, findings that are in line with experimental effects seen for non-specific src inhibitors such as bosutinib or LCB-03-0110 (3). Inhibition of src kinases has been suggested by non-clinical evidence as a potential method of therapy for the pulmonary vascular remodeling and right ventricular hypertrophy in pulmonary hypertension (4), although several reports indicate that dual Abl/src inhibitor dasatinib may actually induce pulmonary hypertension (5)(6)(7); it was more recently suggested that this dasatinib effect may in fact be independent of the src inhibition (7). This family of kinases has been recently shown to be involved in the subgenomic RNA translation and replication of alpha-viruses, their inhibition being suggested as a potentially effective way of treating infections with such viral particles (8).…”

Section: Introductionmentioning

confidence: 72%

Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-Src Tyrosine Kinase

Ancuceanu

Tamba

Stoicescu³

et al. 2019

Preprint

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Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds). 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using Vina and Ledock, and a number of 90 were predicted to be active based on the binding energy. External data from CHEMBL and PUBCHEM confirmed that at least 7.83% (in the case of QSAR) or 6.67% (in the case of integrated QSAR and molecular docking) of the compounds are active on the c-src target.

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“…Moreover, mTOR is one of the intermediates produced during TG synthesis, and mTOR signaling is activated in response to physiological and pathological stimuli, e.g., hemodynamic changes secondary to pressure overload, and leads to a global increase in protein synthesis [14]. Studies have reported the important regulatory role of mTOR both in cardiac hypertrophy and pulmonary vascular remodeling [17][18][19]. In our study, KEGG enrichment analysis showed that both insulin resistance and mTOR were activated at 9 W after TAC surgery.…”

Section: Discussionmentioning

confidence: 99%

Dysfunctional Insulin Resistant/mTOR Activation Is Involved In The Formation of Pulmonary Hypertension In Pressure Overload-Induced Heart Failure

Wu¹,

Dong²,

Ni³

et al. 2021

Preprint

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Background: Heart failure (HF) usually presents with abnormal changes of metabolisms. Pulmonary hypertension (PH) is a frequent complication of left heart dysfunction. However, the association of serum metabolic changes with PH formation remains unknown. This study analyzed changes of serum metabolomic during the development of PH in a left heart pressure overload model. Methods: Male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) or sham surgery. Metabolomic analysis was performed on plasma samples of rats at 0 week, 3 weeks and 9 weeks after the surgery. Cardiac remodeling and heart function were determined by echocardiography. Right heart catheterization was performed to assay the mean pulmonary arterial pressure (mPAP). HE staining was performed to observe the remodeling of the myocardium and small pulmonary arteries.Results: The rats developed compensated cardiac hypertrophy with normal mPAP at 3 weeks and PH due to HF (PH-HF) at 9 weeks with distinct metabolic pattern after TAC. Twenty-five metabolites changed in the 9-week group compared with the 3-week group. KEGG analysis suggested abnormal insulin resistance and mTOR activation during the development of PH-HF. Acetylcarnitines related to insulin resistance increased about 3 folds from 4.14 ug/ml at 3 W group to 12.04μg/ml at 9-week group. L-leucine related to mTOR activation increased 1.6-fold with a VIP of 4.08 at 9 W when compared with that of the 3 W group.Conclusions: These results revealed distinct metabolic changes during the development of PH-HF. Dysfunctional insulin resistance and mTOR activation might be involved in the transition from compensated cardiac hypertrophy to PH-HF.

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Inhibition of Src activation reverses pulmonary vascular remodeling in experimental pulmonary arterial hypertension via Akt/mTOR/HIF-1<alpha> signaling pathway

Cited by 39 publications

References 35 publications

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn

Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-Src Tyrosine Kinase

Dysfunctional Insulin Resistant/mTOR Activation Is Involved In The Formation of Pulmonary Hypertension In Pressure Overload-Induced Heart Failure

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