Korean J Physiol Pharmacol.  2025 Jan;29(1):117-126. 10.4196/kjpp.24.284.

Rosuvastatin activates autophagy via inhibition of the Akt/mTOR axis in vascular smooth muscle cells

• Lee S
• Lee DH
• Lee JP
• Han JH

• KMID: 2563505
• DOI: http://doi.org/10.4196/kjpp.24.284

Abstract

The proliferation and migration of vascular smooth muscle cells (VSMCs) are key contributors to the development of atherosclerosis and restenosis. We investigated the impact of rosuvastatin (RSV) on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of VSMCs, with a focus on the Akt/mTORautophagy signaling pathways. The cytotoxicity of RSV was assessed using MTT and annexin V staining, while the proliferation and migration capabilities of PDGF-BBinduced VSMCs were evaluated using MTT and cell migration assays. Confocal microscopy was employed to examine autophagic cell images, and protein expressions were analyzed via Western blotting. Our key findings revealed that RSV inhibited PDGF-BB-induced proliferation and migration of VSMCs, significantly reducing the expression of proliferating cell nuclear antigen and matrix metalloproteinase-2, which are crucial for these processes. RSV also enhanced autophagy in PDGF-BBstimulated cells by inducing the maturation of microtubule-associated protein light chain 3 and increasing the expression of Beclin-1, autophagy related (Atg)3, Atg5, and Atg7. The regulatory effects of RSV on PDGF-BB-induced autophagy, proliferation, and migration were associated with the suppression of the Akt/mTOR signaling pathway. These findings suggest that RSV may have potential therapeutic benefits in preventing and treating vascular diseases by targeting the Akt/mTOR pathway and inducing autophagy.

Keyword

Autophagy; Mammalian target of rapamycin; Protein kinase B; Rosuvastatin calcium; Vascular smooth muscle cell

Figure

• 

  Fig. 1 Effects of RSV on the cell viability and apoptosis in VSMCs. (A) Cell viability measuring by MTT in VSMCs. The cells were treated with RSV (10, 40 and 100 μM) or digitonin (100 μg/ml) for 48 h. A digitonin was used as the positive control (PC). (B) Examination of apoptosis using Annexin V staining in VSMCs. The cells were treated with RSV (10 and 40 μM) or/and PDGF-BB (25 ng/ml) for 48 h. The percentage of indicated each cell population were determined and quantified. Data were analyzed using mean ± SEM. All experimental techniques are described in the Methods section. RSV, rosuvastatin; VSMCs, vascular smooth muscle cells; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PDGF, platelet-derived growth factor. ***p < 0.001; ****p < 0.0001. n = 3 per group.

• 

  Fig. 2 RSV inhibits PDGF-induced VSMCs proliferation and migration. (A) MTT assay for PDGF-BB-treated VSMCs proliferation. The cells were treated with RSV (10, 20, 40 μM), rapamycin (Ra, 100 nM), and PDGF-BB (25 ng/ml) for 48 h. ****p < 0.0001 vs. Con group, #p < 0.05, ####p < 0.0001 vs. PDGF-BB-treated group. (B) Western blot analysis for the protein expression of PCNA in PDGF-BB-treated VSMCs. The cells were treated with RSV (10, 20 and 40 μM) and PDGF-BB (25 ng/ml) for 48 h. ****p < 0.0001 vs. Con group, ##p < 0.01, ###p < 0.001, ####p < 0.0001 vs. PDGF-BB-treated group. (C) Representative images for RSV and PDGF-BB-treated VSMCs migration. The cells were treated with RSV (10, 20 and 40 μM) and PDGF-BB (25 ng/ml) for 48 h. ****p < 0.0001 vs. Con group, ##p < 0.01, ###p < 0.001 vs. PDGF-BB-treated group. Scale bar: 100 μm. (D) Western blot analysis for the protein expression of MMP-2. The cells were treated with RSV (10, 20 and 40 μM) and PDGF-BB (25 ng/ml) for 48 h. ****p < 0.0001 vs. Con group, ###p < 0.001, ####p < 0.0001 vs. PDGF-BB-treated group. Protein expressions were normalized to β‐actin. Data were analyzed using mean ± SEM. All experimental techniques are described in the Methods section. n = 3 per group. RSV, rosuvastatin; PDGF, platelet-derived growth factor; VSMCs, vascular smooth muscle cells; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PCNA, proliferating cell nuclear antigen; MMP-2, matrix metalloproteinase-2.

• 

  Fig. 3 RSV activates autophagic flux in PDGF-BB-stimulated in VSMCs. Western blot analysis for LC3-I/II expression in (A) basal and (B) PDGF-BB-stimulated VSMCs. The cells were treated with RSV (10, 20 and 40 μM) or/and PDGF-BB (25 ng/ml) for 48 h. *p < 0.05 vs. No PDGF-BB-treated group, ##p < 0.01 and ####p < 0.0001 vs. PDGF-BB-treated group. (C) Representative immunostaining image for LC3 and PCNA on RSV and PDGF-BB-stimulated VSMCs. The cells were treated with RSV (40 μM) and PDGF-BB (25 ng/ml) for 48 h. Blue, DAPI; Green, LC3; Red, PCNA. Scale bar: 20 μm. (D) qPCR analysis for Beclin-1, Atg3, Atg5, and Atg7 mRNA expression. The cells were treated with RSV (40 μM) or/and PDGF-BB (25 ng/ml) for 48 h. *p < 0.05, ***p < 0.001, ****p < 0.0001. Data were analyzed using mean ± SEM. All experimental techniques are described in the Methods section. n = 3 per group. RSV, rosuvastatin; PDGF, platelet-derived growth factor; VSMCs, vascular smooth muscle cells; LC3, light chain 3; PCNA, proliferating cell nuclear antigen; DAPI, 4’,6-diamidino-2-phenylindole; qPCR, quantitative polymerase chain reaction; n.s., no significant.

• 

  Fig. 4 RSV inhibits PDGF-BB-induced VSMCs proliferation and migration through Akt and mTOR-mediated autophagy activation. (A) Western blot analysis for Akt and mTOR phosphorylation. The cells were incubated with rapamycin (100 nM, mTOR inhibitor) for 4 h, and added RSV (40 μM) and PDGF-BB (25 ng/ml) for 48 h. (B) Measurement of LC3-I/II expression using specific signal inhibitors in PDGF-BB-stimulated VSMCs. The cells were incubated with RSV (40 μM), U0126 (10 μM, ERK1/2 inhibitor), MK-2206 (10 μM, Akt inhibitor), and added PDGF-BB for 48 h. (C) MTT assay for RSV, MK-2206, and PDGF-BB-stimulated VSMCs proliferation. The cells were incubated with RSV (40 μM), MK-2206 (10 μM, Akt inhibitor), and PDGF-BB (25 ng/ml) for 48 h. ****p < 0.0001 vs. Con group, ####p < 0.0001 vs. PDGF-BB-treated group. (D) Representative images for PDGF-BB-treated VSMCs migration. The cells were incubated with RSV (40 μM), MK-2206 (10 μM, Akt inhibitor) and PDGF-BB (25 ng/ml) for 48 h. ****p < 0.0001 vs. Con group, ####p < 0.0001 vs. PDGF-BB-treated group. Scale bar: 100 μm. (E) Western blot analysis for MMP-2 and PCNA expression. The cells were incubated with RSV (40 μM), MK-2206, and PDGF-BB (25 ng/ml) for 48 h. Data were analyzed using mean ± SEM. All experimental techniques are described in the Methods section. n = 3 per group. RSV, rosuvastatin; PDGF, platelet-derived growth factor; VSMCs, vascular smooth muscle cells; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PCNA, proliferating cell nuclear antigen.

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