Notoginsenoside R1 inhibits Ang II-induced VSMCs migration by upregulating Sirt1 expression
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Pinghong Ming
,
Yongwu Xia
,
Yunhong Liu
,
Rong Zhu
,
Litao Pan
and
Ting Cai
Abstract
Objectives
To investigate whether Notoginsenoside R1 (NGR1) inhibits angiotensin II (Ang II)-induced vascular smooth muscle cells (VSMCs) migration and to elucidate the underlying mechanisms.
Methods
VSMCs migration model were established using 1 μM Ang II treatment. Subsequently, the migration VSMCs were treated with varying concentrations of NGR1 (0, 10, 20, and 40 μM), respectively. A scratch wound assay was performed to assess the migration area of VSMCs, and western blotting assay was used to evaluate the levels of matrix metalloproteinases (MMP-2, MMP-9), p38 MAPK, phosphorylated p38 MAPK, and silent information regulator 1 (Sirt1) proteins.
Results
NGR1 inhibited Ang II-induced VSMCs migration, downregulated migration-related proteins MMP-2, MMP-9, and p38 MAPK phosphorylation, while upregulating Sirt1 in a dose-dependent manner. Furthermore, upregulation Sirt1 effectively inhibited Ang II-induced VSMCs migration and reduced p38 MAPK phosphorylation proteins expression. Notably, upregulation Sirt1 also further enhanced the inhibitory effects of NGR1 on VSMCs migration and decreased MMP-2, MMP-9, and p38 MAPK phosphorylation proteins expression. Conversely, Sirt1 silencing attenuated these effects.
Conclusions
NGR1 inhibits Ang II-induced migration of VSMCs by upregulating Sirt1, which suppresses p38 MAPK phosphorylation, MMP-2 and MMP-9 levels. These findings suggest that NGR1 may serve as a potential therapeutic agent for atherosclerosis.
Introduction
Atherosclerosis, a leading cause of mortality from acute cardiovascular diseases (CVDs), poses a significant threat to human health. VSMCs, integral components of the arterial middle layer, play a crucial role in the onset and progression of atherosclerosis [1]. Following endothelial injury, inflammatory cells infiltrate the vascular wall and release pro-inflammatory factors, prompting endothelial cells to produce adhesion molecules that bind platelets and monocytes, which in turn stimulates VSMCs proliferation and migration into the plaque area, leading to vessel lumen narrowing and serious cardiovascular events [1], [2], [3], [4]. Therefore, strategies to inhibit VSMCs proliferation and migration are vital for slowing atherosclerosis progression.
Ang II, a potent vasoactive peptide, plays a significant role in CVDs development. Beyond its hypertensive effects mediated through vasoconstriction and aldosterone secretion, Ang II is a key mediator of vascular remodeling [5]. It induces VSMC migration and proliferation, contributing to atherosclerosis risk through the activation of signaling pathways such as mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)/Akt [6]. Notably, p38 MAPK phosphorylation is involved in multiple cellular processes, including proliferation, differentiation, ischemia-reperfusion injury, inflammatory response, phenotypic transformation, apoptosis etc. [7], [8], [9], [10], [11]. Therefore, it is of interest whether p38 MAPK phosphorylation regulates Ang II-induced migration of VSMCs. Thus, understanding whether p38 MAPK phosphorylation regulates Ang II-induced VSMC migration is of significant interest.
Sirt1, a crucial and influential member of the sirtuin family of NAD+-dependent deacetylases, plays essential roles in cellular metabolism, stress responses, and aging [12], [13], [14]. Recently, more and more literatures have highlighted that sirt1 is involved in regulating cell migration in various cell types, including epidermal cells, cancer cells, and retinal endothelial cells [15], [16], [17]. Given that p38 MAPK also regulates vascular endothelial cell proliferation, migration, and lumen formation, the interplay between Sirt1 and p38 MAPK in cell migration has garnered increasing attention [18], 19]. For example, Li et al. [20], demonstrated that Sirt1 overexpression reduces p38 MAPK phosphorylation, enhancing neurobehavioral function. Therefore, these findings provide novel insights into the molecular mechanisms by which Sirt1 may regulate p38 MAPK in VSMCs migration.
NGR1, a bioactive component extracted from the total saponins of Panax notoginseng, has demonstrated a wide range of therapeutic properties, including inhibition of cardiomyocyte hypertrophy, protection against vascular ischemia-reperfusion injury, reduction of oxidative stress, improvement of lipid profiles, and attenuation of inflammation [21], [22], [23], [24], [25]. Collectively, these beneficial effects contribute to the alleviation of atherosclerosis progression. Furthermore, NGR1 also effectively inhibits the migration of VSMCs [26]. However, its potential association with Sirt1 and/or p38 MAPK remains unclear. In this study, we specifically investigated the role of Sirt1 in mediating the effects of NGR1 on Ang II-induced VSMC migration. Our aim was to provide novel experimental insights into the therapeutic potential of NGR1 for prevention and treatment of atherosclerosis.
Materials and methods
Cell culture
VSMCs were acquired from the China Center for Type Culture Collection (GDC0632, Wuhan, China). The cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM; 11,965,092, Thermo Fisher, USA), supplemented with 10 % fetal bovine serum (FBS; 16140071, Thermo Fisher, USA), 1 % penicillin/streptomycin (C0222, Beyotime Biotechnology, China), 10 mM HEPES and 10 mM TES. Cells were maintained in a comfortable environment at 37 °C with 5 % (v/v) CO2 to ensure optimal growth conditions.
Cell transfection
Small interfering RNAs (siRNAs) targeting Sirt1 (si-Sirt1-1/2/3) and a nonspecific control of siRNA (si-Sirt1-NC) were synthesized by Sangon Biotech (Shanghai, China). The sequence of siRNAs as shown in Table S1. The silencing efficiency of siRNAs were examined using western blot analysis, as shown in Figure S1. The pcDNA3.1-Sirt1 plasmid was constructed by our group. Transfections were performed using Lipofectamine™ 2000 (11668019, Thermo Fisher, USA) according to the manufacturer’s protocol. Briefly, VSMCs were plated in 6-well plates at a density of 5 × 105 cells per well in complete DMEM medium. Upon reaching 80 % confluence, cells were transfected with siRNA/Lipofectamine™ 2000 or pcDNA3.1-Sirt1/Lipofectamine™ 2000 complexes. For transfection, final concentration of 20 nM siRNA or 1 μg pcDNA3.1-Sirt1 plasmid was mixed with 5 μL Lipofectamine™ 2000 in 250 μL Opti-MEM medium (11058021, Thermo Fisher, USA) and incubated for 20 min at room temperature, respectively. Subsequently, the mixtures were gently added to the cells and cultivated at 37 °C with 5 % CO2 for 6 h, then the medium was replaced with DMEM complete medium to continue incubation for 24 h.
Scratch wound assay
The VSMCs cells were seeded into 6-well plates. When the cells reached peak and valley states, a sterile pipette tip was used to create several uniform scratch wounds in each well. Subsequently, the cells were washed with PBS to eliminate non-adherent cells, followed by stimulation with 1 µM Ang II to induce migration [27]. Finally, the cells were treated with or without NGR1(≥98 % purity, B21099, Shanghai yuanye Biotechnology, China) and either with Sirt1 or si-Sirt1. The VSMCs migration were assessed by capturing images at 0 and 24 h using a microscope (Olympus BX43, Japan). The relative migration area, compared to the initial wound area (0 h), was precisely calculated by ImageJ software (version 1.8.0; National Institutes of Health, USA).
Western blotting
Protein expression levels of MMP2, MMP9, phosphorylated p38 MAPK (Thr180, Tyr182), p38 MAPK, and Sirt1 were measured by Western blotting, with GAPDH serving as loading control. Briefly, VSMCs were lysed in RIPA lysis buffer (89900, Thermo Fisher, USA) supplemented with a Protease and Phosphatase Inhibitor Cocktail (78441, Thermo Fisher, USA) on ice. Total protein concentrations were quantified using a BCA kit (p0010, Beyotime Biotechnology, China). Proteins (20 µg per lane) were separated using 10 % SDS-PAGE gel electrophoresis. Subsequently, transferred to polyvinylidene fluoride (PVDF) membranes by wet-transfer system. The membranes were sealed with 5 % skimmed milk (232100, BD Difco, USA) at room temperature for 1 h to prevent nonspecific binding and incubated overnight at 4 °C with primary antibodies, including anti-MMP2, MMP9, phosphorylated p38 MAPK (Thr180, Tyr182), p38 MAPK, Sirt1 (1:1,000 dilution, ab181286, ab228402, ab195049, ab182453, ab189494, Thermo Fisher, USA), and anti-GAPDH (1:5,000 dilution, ab181602, Thermo Fisher, USA). After washing, the membranes were incubated with a horseradish peroxidase (HRP)-conjugated IgG secondary antibody (1:5,000 dilution, sc-2357, Santa Cruz Biotechnology, USA) at room temperature for 1 h. Protein bands were visualized using an enhanced chemiluminescence (ECL) kit (Thermo Fisher, USA) and quantified by ImageJ software (version 1.8.0; National Institutes of Health, USA).
Statistical analysis
All experiments were performed in triplicate, and the data were expressed as means ± standard deviation (SD). Differences between groups were evaluated using one-way ANOVA, followed by Tukey’s post hoc test. A p-Value of less than 0.05 was deemed statistically significant. Statistical analyses were conducted using OriginPro 2021 (Version 9.8.0.200, Origin Lab, USA).
Results
NGR1 inhibits Ang II-induced VSMCs migration and reduces MMP-2 and MMP-9 expressions
To evaluate the effects of NGR1 on VSMCs migration, 1 µM Ang II was used to induce VSMCs migration [27]. Subsequently, the cells were treated with 1 µM Ang II and varying concentrations of NGR1 (0, 10, 20, and 40 µM) for 24 h. Compared to the control group (0 h), the migration area of VSMCs was significantly increased in the Ang II+0 µM NGR1 group, confirming that Ang II effectively promotes VSMC migration. However, after NGR1 treatment, the area of VSMC migration gradually decreased with increasing NGR1 concentration. This indicates that NGR1 dose-dependently inhibited Ang II-induced VSMC migration, as shown in Figure 1A. In addition, we also investigated the effects of different concentrations of NGR1 on the migration of VSMCs without Ang II stimulation, as illustrated in Figure S2. The results showed no significant differences in the changes of migration area among the groups. This indicates that, in the absence of Ang II stimulation, different concentrations of NGR1 did not exert a significant effect on the migration area of VSMCs.
NGR1 inhibits Ang II-induced VSMCs migration. (A) Effect of different concentrations of NGR1 on the area of Ang II-induced VSMCs migration. (B) Western blot was employed to detect MMP2 and MMP9 proteins in VSMCs following treatment with various concentrations of NGR1. Migration area and protein bands intensity were quantified using image J software. Compared to control group (0 h), ▲p<0.001. Compared to Ang II group (24 h), *p<0.05, **p<0.01, ***p<0.001. Data are presented as mean ± SD from three independent experiments.
To investigate whether NGR1’s inhibition of VSMC migration is associated with MMP-2 and MMP-9 expressions, Western blot analysis was performed. Compared to the control group (0 h), both MMP-2 and MMP-9 protein levels were significantly elevated in the Ang II + 0 µM NGR1 group. However, after NGR1 treatment, the levels of MMP-2 and MMP-9 decreased in a dose-dependent manner with increasing NGR1 concentration. It suggests that Ang II upregulates MMP-2 and MMP-9 expression, while NGR1 inhibits their expression in VSMCs, as depicted in Figure 1B.
NGR1 reduces p38 MAPK phosphorylation and increases Sirt1 levels in VSMCs
To further explore the mechanisms underlying NGR1’s effects, we examined the role of Sirt1 and p38 MAPK phosphorylation in VSMC migration. VSMCs were stimulated with 1 µM Ang II and treated with NGR1 at concentrations of 0, 10, 20, and 40 µM for 24 h. Compared to the control group (0 h), phosphorylated p38 MAPK levels were significantly increased in the Ang II+0 µM NGR1 group, while Sirt1 levels remained unchanged. However, after NGR1 treatment, p38 MAPK phosphorylation levels were decreased and Sirt1 levels were increased in a dose-dependent manner, as illustrated in Figure 2. Notably, total p38 MAPK protein levels remained constant across all groups. Therefore, NGR1 effectively reduced p38 MAPK phosphorylation and enhanced Sirt1 protein levels in VSMCs.
The impact of NGR1 on phosphorylated p38 MAPK (p-P38 MAPK), P38 MAPK, and Sirt1 proteins in Ang II-induced VSMCs migration. Compared to control group (0 h), ▲p<0.001. Compared to Ang II group (24 h), *p<0.05, **p<0.01, ***p<0.001. Data are presented as mean ± SD from three independent experiments.
Sirt1 inhibits Ang II-induced VSMCs migration by reducing p38 MAPK phosphorylation
We conducted a scratch wound assay to assess whether Sirt1 inhibits Ang II-induced VSMC migration by reducing p38 MAPK phosphorylation. The cells were treated with 1 µM Ang II to induce migration [27], followed by transfection with pcDNA3.1-Sirt1 or si-Sirt1. The results revealed that upregulation Sirt1 significantly inhibited VSMCs migration, while downregulation Sirt1 promoted VSMCs migration, as depicted in Figure 3A.
Sirt1 suppresses Ang II-induced VSMCs migration by reducing p38 MAPK phosphorylation. (A) Impact of Sirt1 modulation on Ang II-induced VSMC migration. (B) Impact of Sirt1 upregulation or downregulation on p-P38 MAPK and P38 MAPK. Compared to Ang II group (24 h), *p<0.05, **p<0.01. Data are presented as mean ± SD from three independent experiments.
Western blot analysis confirmed that upregulation Sirt1 reduced p38 MAPK phosphorylation, whereas downregulation Sirt1 increased p38 MAPK phosphorylation, as shown in Figure 3B. But the total p38 MAPK protein levels remained unchanged across all groups. In summary, enhancing Sirt1 effectively inhibits Ang II-induced VSMCs migration by decreasing p38 MAPK phosphorylation.
NGR1 suppresses Ang II-induced VSMCs migration by upregulating Sirt1
To confirm whether NGR1 inhibits VSMCs migration through upregulation Sirt1 and reduction p38 MAPK phosphorylation, we conducted scratch wound assays and Western blot analysis. Compared to the control group (without any treatment for 0 h), the scratch wound assays showed that Ang II effectively promoted VSMCs migration in the Ang II group (only treatment with Ang II for 24 h). However, the migration area of VSMCs was significantly reduced in the NGR1 group (treatment with Ang II and NGR1 for 24 h). When upregulation Sirt1, the inhibitory effect was most pronounced in the Sirt1+NGR1 group (treatment with Ang II, Sirt1 and NGR1 for 24 h). Conversely, knockdown Sirt1 reduced the inhibition of VSMCs migration in the si-Sirt1+NGR1 group (treatment with Ang II, si-Sirt1 and NGR1 for 24 h), as shown in Figure 4A.
NGR1 suppresses Ang II-induced VSMCs migration by upregulation Sirt1 and downregulation p38 MAPK phosphorylation. (A) Impact of Sirt1 presence or absence on NGR1’s inhibition of Ang II-induced VSMCs migration. (B) Impact of Sirt1 presence or absence on NGR1 regulation MMP2, MMP9, p-P38 MAPK, and P38 MAPK proteins. Compared to control group (0 h), ▲p<0.001. Compared to Ang II group (24 h), *p<0.05, **p<0.01, ***p<0.001. Data are presented as mean ± SD from three independent experiments.
Furthermore, we employed Western blotting to evaluate the expression levels of MMP-2, MMP-9, p38 MAPK, and phosphorylated p38 MAPK. The results demonstrated that the levels of MMP-2, MMP-9, and phosphorylated p38 MAPK were significantly elevated in the Ang II group. However, treatment with NGR1 markedly reduced the expression of these proteins in the NGR1 group. In the Sirt1+NGR1 group, upregulation of Sirt1 further potentiated the ability of NGR1 to suppress the expression of MMP-2, MMP-9, and phosphorylated p38 MAPK. Conversely, in the si-Sirt1+NGR1 group, the knockdown of Sirt1 attenuated the inhibitory effects of NGR1 on the expression of these proteins, as illustrated in Figure 4B. Notably, the total p38 MAPK protein levels remained consistent in all experimental groups. These findings demonstrate that NGR1 inhibits Ang II-induced VSMCs migration by upregulating Sirt1 and downregulating p38 MAPK phosphorylation. Upregulation of Sirt1 strengthens NGR1’s ability to suppress the expression levels of MMP-2, MMP-9, and phosphorylated p38 MAPK proteins, while Sirt1 knockdown reduces NGR1’s effects, highlighting the essential role of Sirt1 in mediating NGR1’s anti-migratory effects.
Discussion
VSMCs migration plays a pivotal role in the pathogenesis of atherosclerosis, making its inhibition critical for the prevention and treatment of this disease [1]. MMP-2 and MMP-9 are proteolytic enzymes that play essential roles in regulating cell migration [28], 29]. Following vascular endothelium injury, various growth factors and cytokines stimulate VSMCs to synthesize and secrete MMP-2 and MMP-9, which facilitate extracellular matrix remodeling and cell migration [25], 30]. Thus, targeting the regulation of VSMC migration and the expression of MMP-2 and MMP-9 represents a promising strategy for atherosclerosis intervention.
NGR1 is a medicinal monomer extracted from P. notoginseng, has demonstrated multiple beneficial effects, including lipid-lowering, anti-apoptotic, anti-inflammatory, and antioxidant properties, as well as the inhibition of VSMC migration and proliferation [22], 26]. In this study, we observed that NGR1 effectively inhibited Ang II-induced VSMCs migration in a dose-dependent manner, consistent with the previous findings [26]. Furthermore, NGR1 also reduced the expression of MMP-2 and MMP-9 in a dose-dependent fashion, suggesting that its anti-migratory effects may be mediated through the suppression of these proteins. However, the precise molecular mechanisms underlying these effects remain incompletely understood and warrant further investigation.
p38 MAPK, as a key signaling factor, is involved in regulating various cellular responses, including stress, inflammation, and cell migration [31]. Previous researches have indicated that p38 MAPK phosphorylation is closely linked to cell migration [32], 33]. Additionally, Sirt1, a NAD+ -dependent deacetylase, has been implicated in the regulation of cell migration [34]. In this study, we demonstrated that NGR1 downregulated p38 MAPK phosphorylation and upregulated Sirt1 expression in a dose-dependent manner, indicating its role in modulating VSMC migration, aligning with the results of the above literature [34].
Sirt1, a member of the sirtuin family, significantly impacts cellular processes, such as cell migration [16], 35]. Upregulation of Sirt1 inhibits VSMC proliferation and migration, while its downregulation enhances these processes [36]. Han et al. [37]. also reported that Sirt1 overexpression inhibits VSMC migration, whereas its knockdown increases VSMC migration. Consistent with these findings, our data demonstrates that Sirt1 overexpression significantly attenuates VSMC migration, while Sirt1 knockdown potentiates migratory capacity in VSMC. Moreover, Sirt1 has been shown to mitigate cardiomyocyte apoptosis by inhibiting p38 MAPK phosphorylation, indicating a close relationship between Sirt1 and p38 MAPK phosphorylation [38]. Our findings further support this relationship, demonstrating that increased Sirt1 expression significantly reduces p38 MAPK phosphorylation, while silencing Sirt1 elevates p38 MAPK phosphorylation levels. It suggests that Sirt1 plays a crucial role in regulating VSMC migration through the modulation of p38 MAPK signaling. In conclusion, Sirt1 upregulation can suppress VSMC migration and attenuate p38 MAPK phosphorylation, which is consistent with previous findings reported in the literature [35], 36], 38].
Although previous literatures have established that Sirt1 can inhibit VSMC migration and modulate p38 MAPK phosphorylation [37], 38], it is remain unclear whether NGR1 inhibits VSMC migration by activating Sirt1 to inhibit p38 MAPK phosphorylation. Our findings demonstrated that both NGR1 and Sirt1 significantly reduced the migration area of VSMCs, respectively. Notably, Sirt1 overexpression further enhanced the inhibitory effect of NGR1 on VSMC migration. Conversely, silencing Sirt1 attenuated the anti-migratory effect of NGR1 on VSMC migration. Furthermore, NGR1 significantly reduced the expression of MMP-2, MMP-9 and phosphorylated p38 MAPK, and overexpression of Sirt1 further enhanced this effect. In contrast, silencing of Sirt1 attenuated the inhibitory effect of NGR1 on MMP2, MMP9 and phosphorylated p38 MAPK proteins. These findings align with previous studies revealing that Sirt1 knockdown accelerates cell migration and enhances MMP-2 and MMP-9 expression [18], 36]. In summary, our findings indicate that NRG1 inhibits Ang II-induced VSMCs migration by increasing Sirt1 expression. At the same time, It also decreased p38 MAPK phosphorylation, MMP-2 and MMP-9 protein expression.
Conclusions
In conclusion, this study illustrates that NGR1 effectively inhibits Ang II-induced VSMCs migration by upregulating Sirt1 expression and reducing the phosphorylation of p38 MAPK, as well as the expression of MMP-2 and MMP-9, in a dose-dependent manner. These findings suggest that NGR1 holds promise as a therapeutic agent for preventing VSMCs migration and may offer a novel strategy for the treatment of atherosclerosis.
Funding source: Team-based Medical Science Research Program
Funding source: San ming Project of Medicine in Shenzhen
Award Identifier / Grant number: (Grant No. szzysm202311020)
Funding source: Shenzhen Science and Technology Program
Award Identifier / Grant number: (Grant No. JCYJ20210324131414040)
Funding source: Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen
Award Identifier / Grant number: (Grant No. 2020071)
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Research ethics: The local Institutional Review Board deemed the study exempt from review.
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Informed consent: Not applicable.
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Author contributions: Conception and design–M.P.H., X.Y.W., P.L.T., C.T.; supervision–P.L.T., C.T.; resources–L.Y.H., X.Y.W., P.L.T., C.T.; data collection and/or processing–M.P.H., X.Y.W., L.Y.H., Z.R.; data analysis and/or interpretation–M.P.H., X.Y.W. C.T.; writing–M.P.H., C.T.; critical reviews–M.P.H., X.Y.W., P.L.T., C.T. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: Authors state no conflict of interest.
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Research funding: The authors would like to acknowledge the support of San ming Project of Medicine in Shenzhen (No. szzysm202311020) and Shenzhen Science and Technology Program (No. JCYJ20210324131414040) and the Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen (No. 2020071), Team-based Medical Science Research Program (Grant No. 2024YZZ07) for supporting this study.
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Data availability: Data are available from the corresponding author.
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