Heat shock protein 90 inhibitor AUY922 attenuates platelet-derived growth factor-BB-induced migration and proliferation of vascular smooth muscle cells

Kim, Jisu; Lee, Kang Pa; Kim, Born Sahn; Lee, Sang Ju; Moon, Byung Seok; Baek, Suji

doi:10.4196/kjpp.2020.24.3.241

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…Ox-LDL (80 μg/ml) was treated to primary VSMC for periods of 0, 3, 6, 12, 24 and 48 h and different concentrations of ox-LDL (0, 20, 40, 80, 160 μg/ml) were incubated for 24 h. The experiment was then divided into four groups, including the Control group, ox-LDL ( Li et al, 2014 ) (80 μg/ml, 24 h) group, ox-LDL + Gap 26 ( Wang et al, 2019b ) (Cx43 specific inhibitor, 100 μM pretreatment for 45 min, and then ox-LDL for 24 h,) group, ox-LDL + LY294002 ( Kim et al, 2020 ) (20 μM pretreatment for 30 min and then ox-LDL for 24 h) group, and the Gap 26 group.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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Background Oxidized low-density lipoproteins (ox-LDL) may induce foam cell formation from the vascular smooth muscle cell (VSMC) by inhibiting VSMC autophagy. This process accelerates the formation of atherosclerosis (AS). Connexin 43 (Cx43), which is the most widely distributed connexin in VSMC is associated with autophagy. However, the mechanism of action and the involvement of Cx43 in ox-LDL-inhibited VSMC autophagy remain unclear. Methods The primary VSMC were obtained and identified, before primary VSMC were pretreated with an inhibitor (Cx43-specific inhibitor Gap26 and PI3K inhibitor LY294002) and stimulated with ox-LDL. Results Ox-LDL not only inhibited autophagy in VSMC via downregulation of autophagy-related proteins (such as Beclin 1, LC3B, p62), but also increased Cx43 protein levels. Then we added Gap26 to VSMC in the ox-LDL+Gap26 group, in which autophagy-related proteins were increased and the accumulation of lipid droplets was reduced. These result suggested that an enhanced level of autophagy and an alleviation of lipid accumulation might be caused by inhibiting Cx43 in VSMC. The phosphorylation levels of PI3K, AKT, mTOR were increased by ox-LDL, thus down-regulating autophagy-related proteins. However, this situation was partially reversed by the Gap26. Moreover, Cx43 expression were decreased by LY294002 in ox-LDL-induced VSMCs. Conclusion Inhibiting Cx43 may activate VSMC autophagy to inhibit foam cell formation by inhibiting the PI3K/AKT/mTOR signaling pathway.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Qin

Yang

et al. 2022

PeerJ

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“…Western blotting was performed as previously described [ 17 ]. The A569 cells were seeded (1 × 10 6 cells/mL) in a 100-mm dish.…”

Section: Methodsmentioning

confidence: 99%

Radotinib attenuates TGFβ -mediated pulmonary fibrosis in vitro and in vivo: exploring the potential of drug repurposing

Baek¹,

Kwon

Jeon

et al. 2022

BMC Pharmacol Toxicol

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Background Tyrosine kinase (TK) plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis. Here, we aimed to investigate whether radotinib (Rb) could inhibit pulmonary fibrosis by inhibiting TK in vitro and in vivo. Methods The antifibrotic effects of Rb in transforming growth factor-β (TGF-β)1-stimulated A549 cells were determined using real-time polymerase chain reaction, western blotting, and immunocytochemistry assays. Rb inhibition of bleomycin-induced lung fibrosis in Sprague Dawley (SD) rats was determined by histopathological and immunohistochemical analyses. Rb-interfering metabolites were analyzed using LC-MS/MS. Results Rb concentrations of up to 1000 nM did not affect the viability of A549 cells, but Rb (30 nM) significantly reduced expression of TGF-β1 (10 ng/mL)-induced ECM factors, such as Snail, Twist, and F-actin. Rb also regulated TGF-β1-overexpressed signal cascades, such as fibronectin and α-smooth muscle actin. Furthermore, Rb attenuated the phosphorylation of Smad2 and phosphorylation of kinases, such as, extracellular signal-regulated kinase, and protein kinase B. In the inhibitory test against bleomycin (5 mg/kg)-induced lung fibrosis, the Rb (30 mg/kg/daily)-treated group showed a half-pulmonary fibrosis region compared to the positive control group. In addition, Rb significantly reduced collagen type I and fibronectin expression in the bleomycin-induced fibrotic region of SD rats. Further, the identified metabolite pantothenic acid was not altered by Rb. Conclusion Taken together, these results indicate that Rb inhibits TGF-β1-induced pulmonary fibrosis both in vitro and in vivo. These findings suggest that Rb may be an effective treatment for pulmonary fibrosis-related disorders and idiopathic pulmonary fibrosis.

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“… 10 11 12 Of various growth factors involved in the VSMC phenotype switching, the platelet-derived growth factor (PDGF) is an important growth factor that stimulates synthetic phenotype switching of VSMCs, leading to enhanced VSMC migration and proliferation in the development of atherosclerosis. 11 13 14 Clinically, it was reported that restenosis occurs within the first six months in 30–40% of patients who have previously undergone percutaneous balloon angioplasty. 15 Furthermore, the aberrant proliferation of VSMCs has been considered critical in developing in-stent restenosis, transplant vasculopathy, and vein bypass graft failure.…”

Section: Introductionmentioning

confidence: 99%

Far-Infrared Irradiation Decreases Proliferation in Basal and PDGF-Stimulated VSMCs Through AMPK-Mediated Inhibition of mTOR/p70S6K Signaling Axis

Hwang,

Park,

Cho

2023

J Korean Med Sci

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Background Far-infrared (FIR) irradiation has been reported to improve diverse cardiovascular diseases, including heart failure, hypertension, and atherosclerosis. The dysregulated proliferation of vascular smooth muscle cells (VSMCs) is well established to contribute to developing occlusive vascular diseases such as atherosclerosis and in-stent restenosis. However, the effects of FIR irradiation on VSMC proliferation and the underlying mechanism are unclear. This study investigated the molecular mechanism through which FIR irradiation inhibited VSMC proliferation. Methods We performed cell proliferation and cell death assay, adenosine 5′-triphosphate (ATP) assay, inhibitor studies, transfection of dominant negative (dn)-AMP-activated protein kinase (AMPK) α1 gene, and western blot analyses. We also conducted confocal microscopic image analyses and ex vivo studies using isolated rat aortas. Results FIR irradiation for 30 minutes decreased VSMC proliferation without altering the cell death. Furthermore, FIR irradiation accompanied decreases in phosphorylation of the mammalian target of rapamycin (mTOR) at Ser2448 (p-mTOR-Ser 2448 ) and p70 S6 kinase (p70S6K) at Thr389 (p-p70S6K-Thr 389 ). The phosphorylation of AMPK at Thr172 (p-AMPK-Thr 172 ) was increased in FIR-irradiated VSMCs, which was accompanied by a decreased cellular ATP level. Similar to in vitro results, FIR irradiation increased p-AMPK-Thr 172 and decreased p-mTOR-Ser 2448 and p-p70S6K-Thr 389 in isolated rat aortas. Pre-treatment with compound C, a specific AMPK inhibitor, or ectopic expression of dn-AMPKα1 gene, significantly reversed FIR irradiation-decreased VSMC proliferation, p-mTOR-Ser 2448 , and p-p70S6K-Thr 389 . On the other hand, hyperthermal stimulus (39°C) did not alter VSMC proliferation, cellular ATP level, and AMPK/mTOR/p70S6K phosphorylation. Finally, FIR irradiation attenuated platelet-derived growth factor (PDGF)-stimulated VSMC proliferation by increasing p-AMPK-Thr 172 , and decreasing p-mTOR-Ser 2448 and p-p70S6K-Thr 389 in PDGF-induced in vitro atherosclerosis model. Conclusion These results show that FIR irradiation decreases the basal and PDGF-stimulated VSMC proliferation, at least in part, by the AMPK-mediated inhibition of mTOR/p70S6K signaling axis irrespective of its hyperthermal effect. These observations suggest that FIR therapy can be used to treat arterial narrowing diseases, including atherosclerosis and in-stent restenosis.

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Heat shock protein 90 inhibitor AUY922 attenuates platelet-derived growth factor-BB-induced migration and proliferation of vascular smooth muscle cells

Cited by 6 publications

References 26 publications

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway

Radotinib attenuates TGFβ -mediated pulmonary fibrosis in vitro and in vivo: exploring the potential of drug repurposing

Far-Infrared Irradiation Decreases Proliferation in Basal and PDGF-Stimulated VSMCs Through AMPK-Mediated Inhibition of mTOR/p70S6K Signaling Axis

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