VCAM-1-binding peptide targeted cationic liposomes containing NLRP3 siRNA to modulate LDL transcytosis as a novel therapy for experimental atherosclerosis
Copyright © 2022. Published by Elsevier Inc..
BACKGROUND: Activation of NLRP3 inflammasome accelerates the formation of atherosclerotic plaques. Here, we evaluated the effects of inflammation on the expression of the NLRP3 inflammasome in endothelial cells (ECs).
METHODS: The effect of TNF-α on transcytosis of LDL was measured. VCAM-1 binding peptide targeting cationic liposomes (PCLs) were prepared as siRNA vectors. Methylated NLRP3 siRNA was encapsulated into the PCLs to knock down NLRP3 in vitro and in vivo. In rats with partial carotid ligation, TNF-α-induced LDL retention in the carotid artery endothelium was observed. In ApoE-/- mice, NLRP3 siRNA-PCLs were injected intravenously to observe their effect on the formation of atherosclerosis.
RESULTS: Our results showed that TNF-α upregulated NLRP3 in ECs, promoting the assembly of the NLRP3 inflammasome and processing of pro-IL-1β into IL-1β. Moreover, TNF-α accelerated LDL transcytosis in ECs. Knockdown of NLRP3 prevented TNF-α-induced NLPR3 inflammasome/IL-1β signaling and LDL transcytosis. Using optimized cationic liposomes to encapsulate methylated NLRP3 siRNA, resulting in targeting of VCAM-1-expressing ECs, to knockdown NLRP3, TNF-α-induced NLRP3 inflammasome activation and LDL transcytosis were prevented. Using the partial carotid ligation as an atherosclerosis rat model, we found that local administration of NLRP3 siRNA-PCLs efficiently knocked down NLPR3 expression in the carotid endothelium and dramatically attenuated the deposition of atherogenic LDL in carotid ECs in TNF-α-challenged rats. Furthermore, NLRP3 siRNA-PCLs were injected intravenously in ApoE-/- mice, resulting in reduced plaque formation.
CONCLUSION: These findings established a novel strategy for targeting the NLRP3 inflammasome using NLRP3 siRNA-PCLs to interrupt LDL transcytosis, representing a potential novel therapy for atherosclerosis.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2022 |
---|---|
Erschienen: |
2022 |
Enthalten in: |
Zur Gesamtaufnahme - volume:135 |
---|---|
Enthalten in: |
Metabolism: clinical and experimental - 135(2022) vom: 15. Okt., Seite 155274 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Jia, Xiong [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 08.09.2022 Date Revised 03.10.2022 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.metabol.2022.155274 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM344374955 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM344374955 | ||
003 | DE-627 | ||
005 | 20231226022625.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2022 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.metabol.2022.155274 |2 doi | |
028 | 5 | 2 | |a pubmed24n1147.xml |
035 | |a (DE-627)NLM344374955 | ||
035 | |a (NLM)35917895 | ||
035 | |a (PII)S0026-0495(22)00152-4 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Jia, Xiong |e verfasserin |4 aut | |
245 | 1 | 0 | |a VCAM-1-binding peptide targeted cationic liposomes containing NLRP3 siRNA to modulate LDL transcytosis as a novel therapy for experimental atherosclerosis |
264 | 1 | |c 2022 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 08.09.2022 | ||
500 | |a Date Revised 03.10.2022 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2022. Published by Elsevier Inc. | ||
520 | |a BACKGROUND: Activation of NLRP3 inflammasome accelerates the formation of atherosclerotic plaques. Here, we evaluated the effects of inflammation on the expression of the NLRP3 inflammasome in endothelial cells (ECs) | ||
520 | |a METHODS: The effect of TNF-α on transcytosis of LDL was measured. VCAM-1 binding peptide targeting cationic liposomes (PCLs) were prepared as siRNA vectors. Methylated NLRP3 siRNA was encapsulated into the PCLs to knock down NLRP3 in vitro and in vivo. In rats with partial carotid ligation, TNF-α-induced LDL retention in the carotid artery endothelium was observed. In ApoE-/- mice, NLRP3 siRNA-PCLs were injected intravenously to observe their effect on the formation of atherosclerosis | ||
520 | |a RESULTS: Our results showed that TNF-α upregulated NLRP3 in ECs, promoting the assembly of the NLRP3 inflammasome and processing of pro-IL-1β into IL-1β. Moreover, TNF-α accelerated LDL transcytosis in ECs. Knockdown of NLRP3 prevented TNF-α-induced NLPR3 inflammasome/IL-1β signaling and LDL transcytosis. Using optimized cationic liposomes to encapsulate methylated NLRP3 siRNA, resulting in targeting of VCAM-1-expressing ECs, to knockdown NLRP3, TNF-α-induced NLRP3 inflammasome activation and LDL transcytosis were prevented. Using the partial carotid ligation as an atherosclerosis rat model, we found that local administration of NLRP3 siRNA-PCLs efficiently knocked down NLPR3 expression in the carotid endothelium and dramatically attenuated the deposition of atherogenic LDL in carotid ECs in TNF-α-challenged rats. Furthermore, NLRP3 siRNA-PCLs were injected intravenously in ApoE-/- mice, resulting in reduced plaque formation | ||
520 | |a CONCLUSION: These findings established a novel strategy for targeting the NLRP3 inflammasome using NLRP3 siRNA-PCLs to interrupt LDL transcytosis, representing a potential novel therapy for atherosclerosis | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Atherosclerosis | |
650 | 4 | |a Cationic liposome | |
650 | 4 | |a LDL transcytosis | |
650 | 4 | |a NLRP3 Inflammasome | |
650 | 4 | |a Targeted delivery | |
650 | 7 | |a Apolipoproteins E |2 NLM | |
650 | 7 | |a Inflammasomes |2 NLM | |
650 | 7 | |a Lipoproteins, LDL |2 NLM | |
650 | 7 | |a Liposomes |2 NLM | |
650 | 7 | |a NLR Family, Pyrin Domain-Containing 3 Protein |2 NLM | |
650 | 7 | |a Nlrp3 protein, mouse |2 NLM | |
650 | 7 | |a Nlrp3 protein, rat |2 NLM | |
650 | 7 | |a RNA, Small Interfering |2 NLM | |
650 | 7 | |a Tumor Necrosis Factor-alpha |2 NLM | |
650 | 7 | |a Vascular Cell Adhesion Molecule-1 |2 NLM | |
700 | 1 | |a Bai, Xiangli |e verfasserin |4 aut | |
700 | 1 | |a Yang, Xiaoyan |e verfasserin |4 aut | |
700 | 1 | |a Wang, Ling |e verfasserin |4 aut | |
700 | 1 | |a Lu, Yajing |e verfasserin |4 aut | |
700 | 1 | |a Zhu, Lin |e verfasserin |4 aut | |
700 | 1 | |a Zhao, Ying |e verfasserin |4 aut | |
700 | 1 | |a Cheng, Wenzhuo |e verfasserin |4 aut | |
700 | 1 | |a Shu, Meng |e verfasserin |4 aut | |
700 | 1 | |a Mei, Qiyong |e verfasserin |4 aut | |
700 | 1 | |a Jin, Si |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Metabolism: clinical and experimental |d 1952 |g 135(2022) vom: 15. Okt., Seite 155274 |w (DE-627)NLM000020761 |x 1532-8600 |7 nnns |
773 | 1 | 8 | |g volume:135 |g year:2022 |g day:15 |g month:10 |g pages:155274 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.metabol.2022.155274 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 135 |j 2022 |b 15 |c 10 |h 155274 |