A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction

Liv Weichien Chen; Min Chien Tsai; Ching Yuh Chern; Tien Ping Tsao; Feng Yen Lin; Sy Jou Chen; Pi Fen Tsui; Yao Wen Liu; Hsien Jui Lu; Wan Lin Wu; Wei Shiang Lin; Chien Sung Tsai; Chin Sheng Lin

doi:10.1111/bph.15175

A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction

Liv Weichien Chen, Min Chien Tsai, Ching Yuh Chern, Tien Ping Tsao, Feng Yen Lin, Sy Jou Chen, Pi Fen Tsui, Yao Wen Liu, Hsien Jui Lu, Wan Lin Wu, Wei Shiang Lin, Chien Sung Tsai, Chin Sheng Lin

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

Background and Purpose: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. Experimental Approach: Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by ³H labelling of cholesterol. LDL receptor knockout (Ldlr^−/−) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. Key Results: Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. Conclusion and Implications: Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

Original language	English
Pages (from-to)	5375-5392
Number of pages	18
Journal	British Journal of Pharmacology
Volume	177
Issue number	23
DOIs	https://doi.org/10.1111/bph.15175
Publication status	Published - Dec 2020

ASJC Scopus subject areas

Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1111/bph.15175

Cite this

Chen, L. W., Tsai, M. C., Chern, C. Y., Tsao, T. P., Lin, F. Y., Chen, S. J., Tsui, P. F., Liu, Y. W., Lu, H. J., Wu, W. L., Lin, W. S., Tsai, C. S., & Lin, C. S. (2020). A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction. British Journal of Pharmacology, 177(23), 5375-5392. https://doi.org/10.1111/bph.15175

Chen, LW, Tsai, MC, Chern, CY, Tsao, TP, Lin, FY, Chen, SJ, Tsui, PF, Liu, YW, Lu, HJ, Wu, WL, Lin, WS, Tsai, CS & Lin, CS 2020, 'A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction', British Journal of Pharmacology, vol. 177, no. 23, pp. 5375-5392. https://doi.org/10.1111/bph.15175

@article{2bd3e76a0d8f45eaaa16c0ffa43ef1c6,

title = "A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction",

abstract = "Background and Purpose: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. Experimental Approach: Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3H labelling of cholesterol. LDL receptor knockout (Ldlr−/−) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. Key Results: Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. Conclusion and Implications: Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.",

author = "Chen, {Liv Weichien} and Tsai, {Min Chien} and Chern, {Ching Yuh} and Tsao, {Tien Ping} and Lin, {Feng Yen} and Chen, {Sy Jou} and Tsui, {Pi Fen} and Liu, {Yao Wen} and Lu, {Hsien Jui} and Wu, {Wan Lin} and Lin, {Wei Shiang} and Tsai, {Chien Sung} and Lin, {Chin Sheng}",

note = "Funding Information: We thank Professor Carlos Fernandez‐Hernando and Professor Shih‐Ming Huang for their invaluable comments. We also thank I‐Jou Teng, Yi‐Jhen Huang, Shao‐Fu Shih and Pei‐Wen Liu for their skilful technical assistance. This work is supported by grants from Tri‐Service General Hospital (TSGH‐C107‐007‐007‐S02, TSGH‐C108‐006‐007‐007‐S02 and TSGH‐E‐109206 to C.‐S.L. and TSGH‐E‐109218 and TSGH C108‐069 to S.‐J.C.), Ministry of National Defense‐Medical Affairs Bureau (MAB‐106‐082 to C.‐S.L. and MAB‐106‐102 and MAB‐109‐069 to M.‐C.T.) and Taiwan Ministry of Science and Technology (MOST 105‐2325‐B016‐001 and MOST 106‐2320‐B‐016‐010 to M.‐C.T. and MOST 106‐2314‐B‐016‐038‐MY3 and MOST 108‐3111‐Y‐016‐015 to C.‐S.L.). Funding Information: We thank Professor Carlos Fernandez-Hernando and Professor Shih-Ming Huang for their invaluable comments. We also thank I-Jou Teng, Yi-Jhen Huang, Shao-Fu Shih and Pei-Wen Liu for their skilful technical assistance. This work is supported by grants from Tri-Service General Hospital (TSGH-C107-007-007-S02, TSGH-C108-006-007-007-S02 and TSGH-E-109206 to C.-S.L. and TSGH-E-109218 and TSGH C108-069 to S.-J.C.), Ministry of National Defense-Medical Affairs Bureau (MAB-106-082 to C.-S.L. and MAB-106-102 and MAB-109-069 to M.-C.T.) and Taiwan Ministry of Science and Technology (MOST 105-2325-B016-001 and MOST 106-2320-B-016-010 to M.-C.T. and MOST 106-2314-B-016-038-MY3 and MOST 108-3111-Y-016-015 to C.-S.L.). Publisher Copyright: {\textcopyright} 2020 The British Pharmacological Society",

year = "2020",

month = dec,

doi = "10.1111/bph.15175",

language = "English",

volume = "177",

pages = "5375--5392",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley and Sons Inc.",

number = "23",

}

TY - JOUR

T1 - A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction

AU - Chen, Liv Weichien

AU - Tsai, Min Chien

AU - Chern, Ching Yuh

AU - Tsao, Tien Ping

AU - Lin, Feng Yen

AU - Chen, Sy Jou

AU - Tsui, Pi Fen

AU - Liu, Yao Wen

AU - Lu, Hsien Jui

AU - Wu, Wan Lin

AU - Lin, Wei Shiang

AU - Tsai, Chien Sung

AU - Lin, Chin Sheng

N1 - Funding Information: We thank Professor Carlos Fernandez‐Hernando and Professor Shih‐Ming Huang for their invaluable comments. We also thank I‐Jou Teng, Yi‐Jhen Huang, Shao‐Fu Shih and Pei‐Wen Liu for their skilful technical assistance. This work is supported by grants from Tri‐Service General Hospital (TSGH‐C107‐007‐007‐S02, TSGH‐C108‐006‐007‐007‐S02 and TSGH‐E‐109206 to C.‐S.L. and TSGH‐E‐109218 and TSGH C108‐069 to S.‐J.C.), Ministry of National Defense‐Medical Affairs Bureau (MAB‐106‐082 to C.‐S.L. and MAB‐106‐102 and MAB‐109‐069 to M.‐C.T.) and Taiwan Ministry of Science and Technology (MOST 105‐2325‐B016‐001 and MOST 106‐2320‐B‐016‐010 to M.‐C.T. and MOST 106‐2314‐B‐016‐038‐MY3 and MOST 108‐3111‐Y‐016‐015 to C.‐S.L.). Funding Information: We thank Professor Carlos Fernandez-Hernando and Professor Shih-Ming Huang for their invaluable comments. We also thank I-Jou Teng, Yi-Jhen Huang, Shao-Fu Shih and Pei-Wen Liu for their skilful technical assistance. This work is supported by grants from Tri-Service General Hospital (TSGH-C107-007-007-S02, TSGH-C108-006-007-007-S02 and TSGH-E-109206 to C.-S.L. and TSGH-E-109218 and TSGH C108-069 to S.-J.C.), Ministry of National Defense-Medical Affairs Bureau (MAB-106-082 to C.-S.L. and MAB-106-102 and MAB-109-069 to M.-C.T.) and Taiwan Ministry of Science and Technology (MOST 105-2325-B016-001 and MOST 106-2320-B-016-010 to M.-C.T. and MOST 106-2314-B-016-038-MY3 and MOST 108-3111-Y-016-015 to C.-S.L.). Publisher Copyright: © 2020 The British Pharmacological Society

PY - 2020/12

Y1 - 2020/12

N2 - Background and Purpose: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. Experimental Approach: Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3H labelling of cholesterol. LDL receptor knockout (Ldlr−/−) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. Key Results: Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. Conclusion and Implications: Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

AB - Background and Purpose: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. Experimental Approach: Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3H labelling of cholesterol. LDL receptor knockout (Ldlr−/−) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. Key Results: Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. Conclusion and Implications: Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

UR - http://www.scopus.com/inward/record.url?scp=85088584527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85088584527&partnerID=8YFLogxK

U2 - 10.1111/bph.15175

DO - 10.1111/bph.15175

M3 - Article

C2 - 32579243

AN - SCOPUS:85088584527

SN - 0007-1188

VL - 177

SP - 5375

EP - 5392

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 23

ER -

A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this