Rutaecarpine prevented ox-LDL-induced VSMCs dysfunction through inhibiting overexpression of connexin 43

Wang, Meiling; Wu, Yusi; Yu, Yan-Rong; Yanqi, Fu; Yan, Hang; Wang, Xiaoying; Li, Tingting; Peng, Wei; Luo, Dongmei

doi:10.1016/j.ejphar.2019.03.028

Cited by 18 publications

(11 citation statements)

References 31 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%

“…The increased expression of connexin 43 in intimal VSMC was observed in the early stages of human and mouse atherosclerotic lesions ( Leybaert et al, 2017 ). This effect may be associated with various risk factors for AS, such as ox-LDL ( Wang et al, 2019b ) or angiotensin II ( Lei et al, 2019 ), which may upregulate the expression of Cx43. Recently, studies have demonstrated that there is an important interaction between Cx and autophagy, that is Cx could be used not only as an autophagy substrate, but also an autophagy regulator ( Iyyathurai et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…Rut has obvious antioxidant6 and anti-inflammatory effects 7. Besides, Rut also has a certain cardiovascular protective effect,8 specifically in preventing hypertensive myocardial hypertrophy9 and preventing the dysfunction of vascular smooth muscle cells 10. It is reported that Rut can prevent myocardial ischemia-reperfusion injury in rats by activating capsaicin-sensitive sensory nerves 11.…”

Section: Introductionmentioning

confidence: 99%

<p>Rutaecarpine may improve neuronal injury, inhibits apoptosis, inflammation and oxidative stress by regulating the expression of ERK1/2 and Nrf2/HO-1 pathway in rats with cerebral ischemia-reperfusion injury</p>

Han¹,

Hu²,

Chen³

2019

DDDT

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BackgroundCerebral ischemia-reperfusion (CI/R) injury is a more serious brain injury caused by the recovery of blood supply after cerebral ischemia for a certain period of time. Rutaecarpine (Rut) is an alkaloid isolated from Evodia officinalis with various biological activities. Previous studies have shown that Rut has a certain protective effect on ischemic brain injury, but the specific molecular mechanism is still unknown.MethodsIn this study, a rat model of CI/R was established to explore the effects and potential molecular mechanisms of Rut on CI/R injury in rats.ResultsThe results showed that Rut alleviated neuronal injury induced by CI/R in a dose-dependent manner. Besides, Rut inhibited neuronal apoptosis by inhibiting the activation of caspase 3 and the expression of Bax. In addition, Rut alleviated the inflammatory response and oxidative stress caused by CI/R through inhibiting the production of pro-inflammatory factors (IL-6 and IL-1β), lactate dehydrogenase (LDH), malondialdehyde (MDA) and ROS, and increased the levels of anti-inflammatory factors (IL-4 and IL-10) and superoxide dismutase (SOD). Biochemically, Western blot analyses showed that Rut inhibited the phosphorylation of ERK1/2 and promoted the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway-related proteins (Nrf2, heme oxygenase 1 (HO-1) and NAD (P) H-quinone oxidoreductase 1) in a dose-dependent manner. These results show that Rut may alleviate brain injury induced by CI/R by regulating the expression of ERK1/2 and the activation of Nrf2/HO-1 pathway.ConclusionIn conclusion, these results suggest that Rut may be used as an effective therapeutic agent for damage caused by CI/R.

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“…Oxidized low density lipoprotein (ox-LDL) is a detrimental factor abundant in the early stage of atherosclerosis and has been unveiled to serve as the curcial stimulator for VSMCs phenotype switching and subsequent apoptosis (34,35). In this context, ox-LDL is frequently utlized for the construction of AS-like cell model (36)(37)(38). Here, we also employed ox-LDL to treat VSMCs and found that ox-LDL had a dose-dependent effect on VSMCs proliferation, and treatment with 100 ug/mL ox-LDL could effetively promote the VSMCs proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

MiR-513a-5p Aggravates Atherosclerosis Phenotype by Downregulating TFPI2 in Vitro

Wang¹,

Feng

2021

Preprint

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BackgroundAtherosclerosis (AS) induced cardiology disease is largely associated with morbidity and mortality. The dysfunction of vascular smooth muscle cells (VSMCs) is considered to contribute to the etiology of AS. However, the mechanism underlying VSMCs dysfunction remains largely unclear. Our study aimed to explore novel molecules mediating VSMCs function.MethodsBioinformatical analysis was applied to identify the key miRNAs that was aberrantly expressed in AS mouse and potentially targeted TFPI2. The AS-like cell model was generated by treating VSMCs with ox-LDL. The expression level of miR-513a-5p and TFPI2 in VSMCs and the serum of AS patients was evaluated by RT-qPCR, and the expression level of TFPI2 and PCNA was measured by western blot. The cell viability and migration capacity of VSMCs were determined by CCK-8 and wound healing assay, respectively. The target relationship between miR-513a-5p and TFPI2 was validated by dual-luciferase assay.ResultsMiR-513a-5p was highly expressed while TFPI2 presented a low expression in AS patient serum. Treatment with 100 μg/mL ox-LDL overtly facilitated the cell viability and migration of VSMCs, also promoted miR-513a-5p expression while limit the expression of TFPI2. Moreover, silencing miR-513a-5p inhibited the cell viability, migration and the expression of proliferative marker in ox-LDL treated VSMCs, while inhibition of TFPI2 enhanced that. It was further found that miR-513a-5p could target TFPI2 and silencing miR-513a-5p compromised the aggresive effect of TFPI2 inhibition on the viability and migration ox-LDL treated VSMCs.ConclusionmiR-513a-5p could contribute to the dysfunction of VSMCs in AS through targeting and inhibiting TFPI2.

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Rutaecarpine prevented ox-LDL-induced VSMCs dysfunction through inhibiting overexpression of connexin 43

Cited by 18 publications

References 31 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

<p>Rutaecarpine may improve neuronal injury, inhibits apoptosis, inflammation and oxidative stress by regulating the expression of ERK1/2 and Nrf2/HO-1 pathway in rats with cerebral ischemia-reperfusion injury</p>

MiR-513a-5p Aggravates Atherosclerosis Phenotype by Downregulating TFPI2 in Vitro

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