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Sterol-resistant SCAP Overexpression in Vascular Smooth Muscle Cells Accelerates Atherosclerosis by Increasing Local Vascular Inflammation through Activation of the NLRP3 Inflammasome in Mice

Li, Danyang, Liu, Mihua, Li, Zhe, Zheng, Guo, Chen, Amei, Zhao, Lei, Yang, Ping, Wei, Li, Chen, Yaxi, Ruan, Xiong Z.·2021·Aging and disease
DOI 10.14336/ad.2020.1120PMC PMC8139202
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Figure 1. Evaluation of the SM22 promoter-driven sterol-resistant SCAP (D443N mutant) transgenic mouse model. (A) mRNA expression of SCAP in the aorta, liver and kidney as measured by qRT-PCR. (B) mRNA expression of SREBP2, HMGCoAR, LDLr in the aorta as measured by qRT-PCR. (C) Expression of SCAP in the aorta, liver and kidney as determined by immune-histochemical staining. (D) Representative immunoblots of SCAP protein expression in the aorta, liver and kidney. (E) Double immune?uorescence staining for SCAP and α-SMA in the aortas of SCAPD443N mice and SCAP+/+ mice. (F) Representative immunoblots of n-SREBP2 protein expression in the aorta of SCAPD443N mice and SCAP+/+ mice. The data are presented as the means±SD of 6 independent experiments. *P<0.05, vs. the SCAP+/+ group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.
Figure 1. Evaluation of the SM22 promoter-driven sterol-resistant SCAP (D443N mutant) transgenic mouse model. (A) mRNA expression of SCAP in the aorta, liver and kidney as measured by qRT-PCR. (B) mRNA expression of SREBP2, HMGCoAR, LDLr in the aorta as measured by qRT-PCR. (C) Expression of SCAP in the aorta, liver and kidney as determined by immune-histochemical staining. (D) Representative immunoblots of SCAP protein expression in the aorta, liver and kidney. (E) Double immune?uorescence staining for SCAP and α-SMA in the aortas of SCAPD443N mice and SCAP+/+ mice. (F) Representative immunoblots of n-SREBP2 protein expression in the aorta of SCAPD443N mice and SCAP+/+ mice. The data are presented as the means±SD of 6 independent experiments. *P<0.05, vs. the SCAP+/+ group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.CC BY · PubMed Central
Figure 2. Sterol-resistant SCAP promotes atherosclerotic lesion progression in ApoE-/- mice. (A) Representative images of the aortic root stained with hematoxylin and eosin (H&E). (B) Representative images of the aortic root stained with Oil Red O. (C) Quantification of the lesion cross-sectional area in H&E-stained aortic root sections in (A) (n=5). (D) Quantification of the lesion volume of Oil Red O-stained aortic root sections in (B) (n=5). (E) Representative images of the aortic root stained with Sirius red and Masson’s trichrome stain. (F) Quantification of the content of collagen fibers in the aortic roots (n=5). (G) Serum levels of TC, TG, HDL-C and LDL-C in ApoE-/- mice and SCAPD443N/ApoE-/- mice (n=6). The data are presented as the means±SD of 5 independent experiments. **P<0.01, vs. the ApoE-/- group. (H) mRNA expression of proin?ammatory cytokines (IL-1β, IL-6, IL-18, TNF-α and TNF-β) as measured by qRT-PCR (n=4). (I) mRNA expression of pro-chemokine cytokines (MCP-1, MIP-1α, MIP-1β, MIP-2, CX3CL1 and CCL-5) as measured by qRT-PCR (n=4). The data are presented as the means±SEM of 4 independent experiments. *P<0.05, vs. the ApoE-/- group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.
Figure 2. Sterol-resistant SCAP promotes atherosclerotic lesion progression in ApoE-/- mice. (A) Representative images of the aortic root stained with hematoxylin and eosin (H&E). (B) Representative images of the aortic root stained with Oil Red O. (C) Quantification of the lesion cross-sectional area in H&E-stained aortic root sections in (A) (n=5). (D) Quantification of the lesion volume of Oil Red O-stained aortic root sections in (B) (n=5). (E) Representative images of the aortic root stained with Sirius red and Masson’s trichrome stain. (F) Quantification of the content of collagen fibers in the aortic roots (n=5). (G) Serum levels of TC, TG, HDL-C and LDL-C in ApoE-/- mice and SCAPD443N/ApoE-/- mice (n=6). The data are presented as the means±SD of 5 independent experiments. **P<0.01, vs. the ApoE-/- group. (H) mRNA expression of proin?ammatory cytokines (IL-1β, IL-6, IL-18, TNF-α and TNF-β) as measured by qRT-PCR (n=4). (I) mRNA expression of pro-chemokine cytokines (MCP-1, MIP-1α, MIP-1β, MIP-2, CX3CL1 and CCL-5) as measured by qRT-PCR (n=4). The data are presented as the means±SEM of 4 independent experiments. *P<0.05, vs. the ApoE-/- group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.CC BY · PubMed Central
Figure 3. Sterol-resistant SCAP increases inflammation in advanced atherosclerotic progression. (A) Expression of proin?ammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) in aortas as determined by immunohistochemical staining. (B) Expression of IL-1β and IL-18 in serum as measured by ELISA. (C) Expression of CD68 in aortas as determined by immunohistochemical staining. (D) Double immuno?uorescence staining for α-SMA and PCNA in the aortas of ApoE-/- mice and SCAPD443N/ApoE-/- mice. (E) Representative images of immuno?uorescence staining of ICAM-1 and VCAM-1 proteins in the atherosclerotic lesions of ApoE-/- mice and SCAPD443N/ApoE-/- mice. (F) Representative images of immuno?uorescence staining of SCAP (green) with NLRP3 (red) in the atherosclerotic lesions of ApoE-/- and SCAPD443N/ApoE-/- mice. The data are presented as the means±SD of 5 independent experiments. *P<0.05, vs. the ApoE-/- group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.
Figure 3. Sterol-resistant SCAP increases inflammation in advanced atherosclerotic progression. (A) Expression of proin?ammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) in aortas as determined by immunohistochemical staining. (B) Expression of IL-1β and IL-18 in serum as measured by ELISA. (C) Expression of CD68 in aortas as determined by immunohistochemical staining. (D) Double immuno?uorescence staining for α-SMA and PCNA in the aortas of ApoE-/- mice and SCAPD443N/ApoE-/- mice. (E) Representative images of immuno?uorescence staining of ICAM-1 and VCAM-1 proteins in the atherosclerotic lesions of ApoE-/- mice and SCAPD443N/ApoE-/- mice. (F) Representative images of immuno?uorescence staining of SCAP (green) with NLRP3 (red) in the atherosclerotic lesions of ApoE-/- and SCAPD443N/ApoE-/- mice. The data are presented as the means±SD of 5 independent experiments. *P<0.05, vs. the ApoE-/- group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.CC BY · PubMed Central
Figure 4. Sterol-resistant SCAP overexpression induces the activation of NLRP3 in?ammasomes in VSMCs. (A) Representative immunoblots for NLRP3, Procaspase-1, cleaved caspase-1, IL-1β, and IL-18 in SCAP-overexpressing VSMCs. (B) Expression of IL-1β and IL-18 in VSMC supernatants as measured by ELISA. (C) Immunoblotting of immunoprecipitation with anti-SCAP or anti-NLRP3 in SCAP-overexpressing VSMCs. (D) Representative images of immuno?uorescence staining of NLRP3 (green) or SCAP (green) with Golgi(red) in control and SCAP-overexpressing VSMCs. (E) Representative immunoblot for NLRP3, Pro-caspase-1, cleaved caspase-1, IL-1β, and IL-18 in SCAP-overexpressing VSMCs treated with lycorine for 4 h. (F) Expression of IL-1β and IL-18 in VSMC supernatants as measured by ELISA. (G) Representative images of the immuno?uorescence staining of NLRP3 (green) or SCAP (green) with Golgi (red) in SCAP VSMCs after treatment with lycorine for 4 h. The data are presented as the means±SD of 3 independent experiments. *P<0.05, vs the control group. Statistical significance was calculated for to the biological replicates by 2-tailed Student’s t test.
Figure 4. Sterol-resistant SCAP overexpression induces the activation of NLRP3 in?ammasomes in VSMCs. (A) Representative immunoblots for NLRP3, Procaspase-1, cleaved caspase-1, IL-1β, and IL-18 in SCAP-overexpressing VSMCs. (B) Expression of IL-1β and IL-18 in VSMC supernatants as measured by ELISA. (C) Immunoblotting of immunoprecipitation with anti-SCAP or anti-NLRP3 in SCAP-overexpressing VSMCs. (D) Representative images of immuno?uorescence staining of NLRP3 (green) or SCAP (green) with Golgi(red) in control and SCAP-overexpressing VSMCs. (E) Representative immunoblot for NLRP3, Pro-caspase-1, cleaved caspase-1, IL-1β, and IL-18 in SCAP-overexpressing VSMCs treated with lycorine for 4 h. (F) Expression of IL-1β and IL-18 in VSMC supernatants as measured by ELISA. (G) Representative images of the immuno?uorescence staining of NLRP3 (green) or SCAP (green) with Golgi (red) in SCAP VSMCs after treatment with lycorine for 4 h. The data are presented as the means±SD of 3 independent experiments. *P<0.05, vs the control group. Statistical significance was calculated for to the biological replicates by 2-tailed Student’s t test.CC BY · PubMed Central
Figure 5. Sterol-resistant SCAP overexpression in VSMCs causes inflammation and lipid deposition in the aortas of SCAPD443N mice. (A and B) Representative images of an aortic root stained with Oil Red O in SCAPD443N mice and SCAP+/+ mice after 12 or 24 weeks of Western diet feeding. (C) Quantification of plaque areas in SCAPD443N mice and SCAP+/+ mice after 12 or 24 weeks of Western diet feeding (n=5). (D) Plasma levels of TC, TG, LDL-C and HDL-C in SCAPD443N mice and SCAP+/+ mice after 12 or 24 weeks of Western diet feeding (n=5). (E) mRNA expression of proin?ammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) as measured by qRT-PCR (n=4). (F) mRNA expression of pro-chemokine cytokines (MCP-1, MIP-1α, MIP-1β, and CX3CL1) as measured by qRT-PCR (n=4). (G) mRNA expression of ICAM-1 and VCAM-1 in aortas as measured by qRT-PCR (n=4). (H) Representative immunoblots for NLRP3 proteins in SCAP+/+ mice and SCAPD443N mice (n=3). (I) Representative images of immuno?uorescence staining of NLRP3 proteins in the aortas of SCAPD443N mice and SCAP+/+ mice (n=5). The data are presented as the means±SD of 3-5 independent experiments. *P<0.05, vs. the SCAP+/+ group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.
Figure 5. Sterol-resistant SCAP overexpression in VSMCs causes inflammation and lipid deposition in the aortas of SCAPD443N mice. (A and B) Representative images of an aortic root stained with Oil Red O in SCAPD443N mice and SCAP+/+ mice after 12 or 24 weeks of Western diet feeding. (C) Quantification of plaque areas in SCAPD443N mice and SCAP+/+ mice after 12 or 24 weeks of Western diet feeding (n=5). (D) Plasma levels of TC, TG, LDL-C and HDL-C in SCAPD443N mice and SCAP+/+ mice after 12 or 24 weeks of Western diet feeding (n=5). (E) mRNA expression of proin?ammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) as measured by qRT-PCR (n=4). (F) mRNA expression of pro-chemokine cytokines (MCP-1, MIP-1α, MIP-1β, and CX3CL1) as measured by qRT-PCR (n=4). (G) mRNA expression of ICAM-1 and VCAM-1 in aortas as measured by qRT-PCR (n=4). (H) Representative immunoblots for NLRP3 proteins in SCAP+/+ mice and SCAPD443N mice (n=3). (I) Representative images of immuno?uorescence staining of NLRP3 proteins in the aortas of SCAPD443N mice and SCAP+/+ mice (n=5). The data are presented as the means±SD of 3-5 independent experiments. *P<0.05, vs. the SCAP+/+ group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.CC BY · PubMed Central
Figure 6. VSMCs overexpressing sterol-resistant SCAP promotes endothelial dysfunction by inducing inflammation. SCAP-overexpressing VSMC-conditioned media (SCAP CM) were collected from SCAP-overexpressing VSMCs. (A and B) Expression of ICAM-1 and VCAM-1 in aortas as determined by immunohistochemical staining. (C and D) Flow cytometry analysis of endothelial cell apoptosis after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h, and apoptosis in endothelial cells was quantified. (E) The mRNA expression of ICAM-1 and VCAM-1 in endothelial cells after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h was measured by qRT-PCR. (F and G) Representative images of immuno?uorescence staining of ICAM-1 and VCAM-1 proteins in endothelial cells after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h. (H) Representative images of THP1 monocytes (small, round cells) adhered to endothelial cells (cobblestone shape) after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h. (I) Expression of ICAM-1 and VCAM-1 protein in endothelial cells after exposure to WT CM or SCAP CM with LDL for 24 h as measured by Western blotting. The data are presented as the means±SD of 3 independent experiments. *P<0.05, vs. the WT CM+LDL group, #P<0.05, vs. the SCAP CM group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.
Figure 6. VSMCs overexpressing sterol-resistant SCAP promotes endothelial dysfunction by inducing inflammation. SCAP-overexpressing VSMC-conditioned media (SCAP CM) were collected from SCAP-overexpressing VSMCs. (A and B) Expression of ICAM-1 and VCAM-1 in aortas as determined by immunohistochemical staining. (C and D) Flow cytometry analysis of endothelial cell apoptosis after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h, and apoptosis in endothelial cells was quantified. (E) The mRNA expression of ICAM-1 and VCAM-1 in endothelial cells after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h was measured by qRT-PCR. (F and G) Representative images of immuno?uorescence staining of ICAM-1 and VCAM-1 proteins in endothelial cells after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h. (H) Representative images of THP1 monocytes (small, round cells) adhered to endothelial cells (cobblestone shape) after exposure to WT CM or SCAP CM with 100 μg/ml of LDL for 24 h. (I) Expression of ICAM-1 and VCAM-1 protein in endothelial cells after exposure to WT CM or SCAP CM with LDL for 24 h as measured by Western blotting. The data are presented as the means±SD of 3 independent experiments. *P<0.05, vs. the WT CM+LDL group, #P<0.05, vs. the SCAP CM group. Statistical significance was calculated for the biological replicates by 2-tailed Student’s t test.CC BY · PubMed Central
Figure 7. Inhibition of SCAP translocation ameliorates endothelial dysfunction by reducing NLRP3 in?ammasome activation. SCAP CM were collected from SCAP-overexpressing VSMCs after 4 h of treatment with or without lycorine. HUVECs were grown to confluence, and then HUVECs were treated with SCAP CM and 100 μg/ml of LDL for 24 h. (A) Flow cytometry analysis of endothelial cell apoptosis. (B) Representative images of immuno?uorescence staining of ICAM-1 and VCAM-1 proteins in endothelial cells. (C) Expression of ICAM-1 and VCAM-1 protein in endothelial cells as measured by Western blotting. (D) Quantification of ICAM-1 and VCAM-1 protein in endothelial cells in (C). (E) SCAP overexpression in VSMCs enhances local inflammation in the aorta via upregulation of NLRP3 expression and synergizes with hypercholesterolemia to promote endothelial dysfunction, which is implicated in atherosclerotic lesion initiation and progression. The data are presented as the means±SD of 3 independent experiments. *P<0.05, vs. the SCAP CM+LDL group. The data were tested using two-way analysis of variance, followed by Q-tests.
Figure 7. Inhibition of SCAP translocation ameliorates endothelial dysfunction by reducing NLRP3 in?ammasome activation. SCAP CM were collected from SCAP-overexpressing VSMCs after 4 h of treatment with or without lycorine. HUVECs were grown to confluence, and then HUVECs were treated with SCAP CM and 100 μg/ml of LDL for 24 h. (A) Flow cytometry analysis of endothelial cell apoptosis. (B) Representative images of immuno?uorescence staining of ICAM-1 and VCAM-1 proteins in endothelial cells. (C) Expression of ICAM-1 and VCAM-1 protein in endothelial cells as measured by Western blotting. (D) Quantification of ICAM-1 and VCAM-1 protein in endothelial cells in (C). (E) SCAP overexpression in VSMCs enhances local inflammation in the aorta via upregulation of NLRP3 expression and synergizes with hypercholesterolemia to promote endothelial dysfunction, which is implicated in atherosclerotic lesion initiation and progression. The data are presented as the means±SD of 3 independent experiments. *P<0.05, vs. the SCAP CM+LDL group. The data were tested using two-way analysis of variance, followed by Q-tests.CC BY · PubMed Central

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Metadata

Authors
Li, D., Liu, M., Li, Z., Zheng, G., Chen, A., Zhao, L., Yang, P., Wei, L., Chen, Y., & Ruan, X. Z.
Venue
Aging and disease
Publisher
Aging and Disease
Published
2021
Volume
12
Issue
3
Pages
747
ISSN
2152-5250
DOI
10.14336/ad.2020.1120
PMC
PMC8139202
Cited by
26
References
3
Language
en

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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CoChat. (2026). Citation check: Sterol-resistant SCAP Overexpression in Vascular Smooth Muscle Cells Accelerates Atherosclerosis by Increasing Local Vascular Inflammation through Activation of the NLRP3 Inflammasome in Mice. https://app.cochat.ai/papers/10.14336/ad.2020.1120
The paper
Li, D., Liu, M., Li, Z., Zheng, G., Chen, A., Zhao, L., Yang, P., Wei, L., Chen, Y., & Ruan, X. Z. (2021). Sterol-resistant SCAP Overexpression in Vascular Smooth Muscle Cells Accelerates Atherosclerosis by Increasing Local Vascular Inflammation through Activation of the NLRP3 Inflammasome in Mice. Aging and disease. https://doi.org/10.14336/ad.2020.1120