1521-0081/71/4/596–670$35.00 https://doi.org/10.1124/pr.118.017178 PHARMACOLOGICAL REVIEWS Pharmacol Rev 71:596–670, October 2019 Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: QIANG MA Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products Dongdong Wang, Yang Yang, Yingnan Lei, Nikolay T. Tzvetkov, Xingde Liu, Andy Wai Kan Yeung, Suowen Xu, and Atanas G. Atanasov The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China (D.W., X.L.); Department of Molecular Biology, Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrze˛biec, Poland (D.W., Y.Y., Y.L., A.G.A.); Department of Pharmacognosy, University of Vienna, Vienna, Austria (A.G.A.); Institute of Clinical Chemistry, University Hospital Zurich, Schlieren, Switzerland (D.W.); Institute of Molecular Biology “Roumen Tsanev,” Department of Biochemical Pharmacology and Drug Design, Bulgarian Academy of Sciences, Sofia, Bulgaria (N.T.T.); Pharmaceutical Institute, University of Bonn, Bonn, Germany (N.T.T.); Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, New York (S.X.); Oral and Maxillofacial Radiology, Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China (A.W.K.Y.); and Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria (A.G.A.) Abstract ....................................................................................599 I. Atherosclerosis: An Introduction ............................................................599 II. Foam Cell Formation as a Hallmark of Atherosclerosis . .....................................600 A. Cholesterol Uptake . ..................................................................600 Downloaded from 1. CD36..............................................................................601 2. Macrophage Scavenger Receptor 1 . ................................................603 3. Lectin-like Oxidized Low-density Lipoprotein Receptor-1 . .........................604 4. Others .............................................................................605 B. Cholesterol Esterification and Hydrolysis................................................605 by guest on September 24, 2021 1. Acetyl-CoA Acetyltransferases 1 and Acetyl-CoA Acetyltransferases 2 . .............605 2. Neutral Cholesterol Ester Hydrolase 1 ..............................................606 3. Lysosomal Acid Lipase (Lipase A) and Hormone-sensitive Lipase 1 (Lipase E) .......606 C. Macrophage Cholesterol Efflux ..........................................................607 1. Aqueous Diffusion Efflux Pathway . ................................................607 2. Transporter-Dependent Cholesterol Efflux Pathway . ...............................607 a. ATP-binding Cassette Transporter A1 . ..........................................607 b. ATP-binding Cassette Transporter G1 . ..........................................610 c. Scavenger Receptor Class B Type 1..............................................611 3. Acceptors that Mediate Macrophage Cholesterol Efflux ..............................612 a. Apolipoprotein A-1 . ............................................................612 b. High-density Lipoprotein . ......................................................614 c. Apolipoprotein E ................................................................614 III. Models for Studying Foam Cell Formation . ................................................615 A. Cellular Models. ........................................................................615 1. Models for Studying Cholesterol Uptake . ..........................................615 2. Models for Studying Cholesterol Efflux..............................................616 a. Loading cells with labeled lipids to form foam cells ..............................616 b. Inducing cholesterol efflux to extracellular acceptors and quantification . .......617 B. Animal Models for Studying Foam Cell Formation. .....................................618 Address correspondence to: Dr. Atanas G. Atanasov, Department of Molecular Biology, Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, ul. Postepu 36A, Jastrze˛biec, 05-552 Magdalenka, Poland. E-mail: [email protected] and [email protected]; or Dr. Suowen Xu, Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, NY, 14623. E-mail: [email protected] and [email protected] This work was supported by the Cultivation Project for Clinical Medicine of the Integrated Traditional Chinese and Western Medicine and Cultivation Project for Education team of internal medicine of the integrated traditional Chinese and western medicine in the first-term subjects, with special support from the first-class universities in Guizhou province [Qin Jiao Gao Fa No. 2017-158], Polish KNOW (Leading National Research Centre) Scientific Consortium “Healthy Animal-Safe Food” [decision of Ministry of Science and Higher Education No. 05-1/KNOW2/2015], and the Peter und Traudl Engelhorn Foundation for the promotion of Life Sciences. S.X. is supported by American Heart Association Career Development Award [18CDA34110359]. https://doi.org/10.1124/pr.118.017178. 596 Targeting Foam Cells by Natural Products 597 IV. Natural Products Targeting Foam Cell Formation in Atherosclerosis.........................619 A. Flavonoids..............................................................................619 1. Alpinetin. ........................................................................619 2. Anthocyanin. .......................................................................619 3. Baicalin ............................................................................633 4. Chrysin ............................................................................634 5. Cyanidin-3-O-b-glucoside ...........................................................634 6. Daidzein . ........................................................................634 7. Ellagic Acid ........................................................................634 8. Hesperetin . ........................................................................635 9. Icariin .............................................................................635 10. Iris Isoflavones . ..................................................................635 11. Pratensein . ........................................................................635 12. Puerarin . ........................................................................635 13. Quercetin . ........................................................................636 14. Silymarin . ........................................................................636 15. Wogonin . ........................................................................636 B. Terpenoids .............................................................................636 1. Carotenoids ........................................................................636 a. Astaxanthin. ..................................................................636 b. Capsanthin . ..................................................................637 c. b-Carotene......................................................................637 d. Retinoids .......................................................................637 e. Lycopene .......................................................................637 2. Ursolic Acid ........................................................................638 3. Betulinic Acid ......................................................................638 4. Erythrodiol. ........................................................................638 5. Ginsenosides .......................................................................638 6. Saikosaponin A. ..................................................................639 7. Tanshinone IIA . ..................................................................639 8. Tanshindiol C ......................................................................639 9. Zerumbone . ........................................................................639 ABBREVIATIONS: ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; AC, anthocyanins; ACAT, acetyl-CoA acetyltransferases; acLDL, acetylated LDL; AMPK, AMP-activated protein kinase; AP-1, activating protein-1; ApoA-1, apolipo- protein A-1; ApoE, apolipoprotein E; APS, astragalus polysaccharides; ATRA, all-trans retinoic acid; BET, extra terminal bromodomains; BMDMs, bone marrow-derived macrophages; BODIPY, dipyrromethene boron difluoride; C3G, cyanidin-3-O-glucoside; CAD, coronary artery disease; CE, cholesterol esters; CETP, cholesteryl ester transfer protein; 9-cis-bc, 9-cis-b-carotene; CLA-1, clarinet 1; CVD, cardiovascular disease; CXCL16, C-X-C motif chemokine ligand 16; DHA, docosahexaenoic acid; DiI, 1,19-dioctadecyl-3,3,39,39-tetra-methylindocyanide percholorate; EGCG, epigallocatechin gallate; eNOS, endothelial NO synthase; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; FC, free cholesterol; F-Ch, fluorophore Pennsylvania green/N-alkyl-3b-cholesterylamine-derived molecular probe; GLP-1, glucagon-like peptide-1; HDL, high-density lipoprotein; HDL-C, HDL-cholesterol; HFD, high fat diet; HMDM, human monocyte-derived macrophages;