Angiogenesis, Inflammation & Therapeutics | Online ISSN  2207-872X
REVIEWS   (Open Access)

Unlocking the Potential of Pig Models in Atherosclerosis Research: Insights, Applications, and Future Directions

Anastasia V. Poznyak 1*, Alexey V. Churov 2,3, Arthur A. Lee 3,4, Dmitry F. Beloyartsev 3, Tatiana Ivanovna Kovynova 1,3, Vasily N. Sukhorukov 3,4, Alexander N. Orekhov 3,4*

+ Author Affiliations

Journal of Angiotherapy 8(7) 1-12 https://doi.org/10.25163/angiotherapy.879732

Submitted: 19 May 2024  Revised: 24 July 2024  Published: 27 July 2024 

This review describes the understanding of atherosclerosis through animal models aids in revealing disease mechanisms, testing treatments, and improving therapeutic strategies for humans.

Abstract


Background: Choosing an adequate model for studying human diseases, such as atherosclerosis, poses significant challenges. While small animals like mice and rats have been widely employed, the suitability of these models for specific research goals and objectives may vary. Furthermore, differences in lipid physiology and platelet quantities between rodents and humans can impact the translational relevance of findings. Large animal models, particularly swine, offer physiological similarities to humans and present a more accurate representation of clinical complications such as acute myocardial infarction and stroke. Objectives: This review aims to comprehensively evaluate the utility of the swine model in atherosclerosis research by examining the physiological and cardiovascular similarities between swine and humans. It also seeks to explore the significance of hyperlipidemia and atherosclerosis in pigs, considering both natural and genetically engineered mutant pig models. Additionally, the review aims to provide an overview of the potential applications of swine models in atherosclerosis regression research, thereby highlighting the advantages and limitations of employing swine in atherosclerosis studies. Conclusion: This review offers insights into the potential of the swine model as a valuable and versatile tool for expanding the horizons of atherosclerosis research, emphasizing the need for further exploration and utilization of large animal models in cardiovascular research.

Keywords: Atherosclerosis, LDL oxidation, Inflammation, Animal models, Plaque progression

References


Aiello, R. J., Nevin, D. N., Ebert, D. L., Uelmen, P. J., Kaiser, M. E., MacCluer, J. W., Blangero, J., Dyer, T. D., & Attie, A. D. (1994). Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, 14(3), 409–419. https://doi.org/10.1161/01.atv.14.3.409

Alban, L., Petersen, J. V., & Busch, M. E. (2015). A comparison between lesions found during meat inspection of finishing pigs raised under organic/free-range conditions and conventional, indoor conditions. Porcine Health Management, 1, 4. https://doi.org/10.1186/2055-5660-1-4

Artinger, S., Deiner, C., Loddenkemper, C., Schwimmbeck, P. L., Schultheiss, H. P., & Pels, K. (2009). Complex porcine model of atherosclerosis: Induction of early coronary lesions after long-term hyperlipidemia without sustained hyperglycemia. The Canadian Journal of Cardiology, 25(4), e109–e114. https://doi.org/10.1016/s0828-282x(09)70068-6

Berger, J. S., & Seeger, J. (2015). The role of high-sensitivity C-reactive protein in predicting cardiovascular events. JAMA Internal Medicine, 175(10), 1749–1757. https://doi.org/10.1001/jamainternmed.2015.4410

Bornfeldt, K. E., & Tabas, I. (2011). Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metabolism, 14(5), 575–586. https://doi.org/10.1016/j.cmet.2011.10.006

Bray, M. A., Sartain, S. E., Gollamudi, J., & Rumbaut, R. E. (2020). Microvascular thrombosis: Experimental and clinical implications. Translational Research: The Journal of Laboratory and Clinical Medicine, 225, 105–130. https://doi.org/10.1016/j.trsl.2020.05.006

Chiu, J. J., & Chien, S. (2011). Effects of disturbed flow on vascular endothelium: Pathophysiological basis and clinical perspectives. Physiological Reviews, 91(1), 327–387. https://doi.org/10.1152/physrev.00047.2009

Cook-Mills, J. M., Marchese, M. E., & Abdala-Valencia, H. (2011). Vascular cell adhesion molecule-1 expression and signaling during disease: Regulation by reactive oxygen species and antioxidants. Antioxidants & Redox Signaling, 15(6), 1607–1638. https://doi.org/10.1089/ars.2010.3522

Diaz, J. A., Obi, A. T., Myers, D. D., Jr, Wrobleski, S. K., Henke, P. K., & Wakefield, T. W. (2020). Animal models of venous thrombosis: Current approaches and future directions. Thrombosis Research, 193, 103–111. https://doi.org/10.1016/j.thromres.2020.08.005

Engelberg, J. A., & Ramaswamy, K. (2015). Animal models of thrombotic disease: Applications in drug discovery and development. Drug Discovery Today, 20(5), 585–594. https://doi.org/10.1016/j.drudis.2014.12.004

Fan, J., Kitajima, S., Watanabe, T., Xu, J., Zhang, J., Liu, E., & Chen, Y. E. (2015). Rabbit models for the study of human atherosclerosis: From pathophysiological mechanisms to translational medicine. Pharmacology & Therapeutics, 146, 104–119. https://doi.org/10.1016/j.pharmthera.2014.09.009

Farnier, M. (2013). PCSK9 inhibitors. Current Opinion in Lipidology, 24(3), 251–258. https://doi.org/10.1097/MOL.0b013e3283613a3d

Fioranelli, M., Bottaccioli, A. G., Bottaccioli, F., Bianchi, M., Rovesti, M., & Roccia, M. G. (2018). Stress and inflammation in coronary artery disease: A review psychoneuroendocrineimmunology-based. Frontiers in Immunology, 9, 2031. https://doi.org/10.3389/fimmu.2018.02031

Frostegård, J. (2013). Immunity, atherosclerosis and cardiovascular disease. BMC Medicine, 11, 117. https://doi.org/10.1186/1741-7015-11-117

Gertz, S. D., Mintz, Y., Beeri, R., Rubinstein, C., Gilon, D., Gavish, L., Berlatzky, Y., Appelbaum, L., & Gavish, L. (2013). Lessons from animal models of arterial aneurysm. Aorta (Stamford, Conn.), 1(5), 244–254. https://doi.org/10.12945/j.aorta.2013.13-052

Getz, G. S., & Reardon, C. A. (2022). Pig and mouse models of hyperlipidemia and atherosclerosis. Methods in Molecular Biology (Clifton, N.J.), 2419, 379–411. https://doi.org/10.1007/978-1-0716-1924-7_24

Gimbrone, M. A., Jr, & García-Cardeña, G. (2016). Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circulation Research, 118(4), 620–636. https://doi.org/10.1161/CIRCRESAHA.115.306301

Glagov, S., Bassiouny, H. S., Sakaguchi, Y., Goudet, C. A., & Vito, R. P. (1997). Mechanical determinants of plaque modeling, remodeling and disruption. Atherosclerosis, 131(Suppl), S13–S14. https://doi.org/10.1016/s0021-9150(97)06117-0

Grundy, S. M., Cleeman, J. I., Daniels, S. R., Donato, K. A., Eckel, R. H., Franklin, B. A., Gordon, D. J., Krauss, R. M., Savage, P. J., & Smith, S. C., Jr. (2005). Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation, 112(17), 2735–2752. https://doi.org/10.1161/CIRCULATIONAHA.105.169404

Harris, K. B., Pond, W. G., Mersmann, H. J., Smith, E. O., Cross, H. R., & Savell, J. W. (2004). Evaluation of fat sources on cholesterol and lipoproteins using pigs selected for high or low serum cholesterol. Meat Science, 66(1), 55–61. https://doi.org/10.1016/S0309-1740(03)00012-3

Ho, F., Watson, A. M. D., Elbatreek, M. H., Kleikers, P. W. M., Khan, W., Sourris, K. C., Dai, A., Jha, J., Schmidt, H. H. H. W., & Jandeleit-Dahm, K. A. M. (2022). Endothelial reactive oxygen-forming NADPH oxidase 5 is a possible player in diabetic aortic aneurysm but not atherosclerosis. Scientific Reports, 12(1), 11570. https://doi.org/10.1038/s41598-022-15706-5

Jenkins, A., Januszewski, A., & O'Neal, D. (2019). The early detection of atherosclerosis in type 1 diabetes: Why, how and what to do about it. Cardiovascular Endocrinology & Metabolism, 8(1), 14–27. https://doi.org/10.1097/XCE.0000000000000169

Jiang, L., Wang, L. Y., & Cheng, X. S. (2018). Novel approaches for the treatment of familial hypercholesterolemia: Current status and future challenges. Journal of Atherosclerosis and Thrombosis, 25(8), 665–673. https://doi.org/10.5551/jat.43372

Kavurma, M. M., Rayner, K. J., & Karunakaran, D. (2017). The walking dead: Macrophage inflammation and death in atherosclerosis. Current Opinion in Lipidology, 28(2), 91–98. https://doi.org/10.1097/MOL.0000000000000394

Khan, N., Ali, S., & Rizvi, S. I. (2018). Animal models for studying atherosclerosis and the role of antioxidants. Advanced Biomedical Research, 7, 63. https://doi.org/10.4103/2277-9175.235056

Khatana, C., Saini, N. K., Chakrabarti, S., Saini, V., Sharma, A., Saini, R. V., & Saini, A. K. (2020). Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis. Oxidative Medicine and Cellular Longevity, 2020, 5245308. https://doi.org/10.1155/2020/5245308

Kobari, Y., Koto, M., & Tanigawa, M. (1991). Regression of diet-induced atherosclerosis in Göttingen miniature swine. Laboratory Animals, 25(2), 110–116. https://doi.org/10.1258/002367791781082478

Kojima, Y., Weissman, I. L., & Leeper, N. J. (2017). The role of efferocytosis in atherosclerosis. Circulation, 135(5), 476–489. https://doi.org/10.1161/CIRCULATIONAHA.116.025684

Koster, A., Blankenberg, S., van der Meer, F. J., Dullaart, R. P., & Schouten, J. S. (2020). Blood biomarkers for atherosclerosis risk assessment: An update on recent advancements. Journal of Clinical Medicine, 9(6), 1958. https://doi.org/10.3390/jcm9061958

Kretz, C. A., Vaezzadeh, N., & Gross, P. L. (2010). Tissue factor and thrombosis models. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(5), 900–908. https://doi.org/10.1161/ATVBAHA.108.177477

Lanfranco, M. F., Ng, C. A., & Rebeck, G. W. (2020). ApoE lipidation as a therapeutic target in Alzheimer's disease. International Journal of Molecular Sciences, 21(17), 6336. https://doi.org/10.3390/ijms21176336

Lee, Y. T., Laxton, V., Lin, H. Y., Chan, Y. W. F., Fitzgerald-Smith, S., To, T. L. O., Yan, B. P., Liu, T., & Tse, G. (2017). Animal models of atherosclerosis. Biomedical Reports, 6(3), 259–266. https://doi.org/10.3892/br.2017.843

Linton, M. R. F., Yancey, P. G., Davies, S. S., et al. (2019, January 3). The role of lipids and lipoproteins in atherosclerosis. In K. R. Feingold, B. Anawalt, M. R. Blackman, et al. (Eds.), Endotext. South Dartmouth, MA: MDText.com, Inc. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK343489/

Ludvigsen, T. P., Kirk, R. K., Christoffersen, B. Ø., Pedersen, H. D., Martinussen, T., Kildegaard, J., Heegaard, P. M., Lykkesfeldt, J., & Olsen, L. H. (2015). Göttingen minipig model of diet-induced atherosclerosis: Influence of mild streptozotocin-induced diabetes on lesion severity and markers of inflammation evaluated in obese, obese and diabetic, and lean control animals. Journal of Translational Medicine, 13, 312. https://doi.org/10.1186/s12967-015-0670-2

Maestro, S., Weber, N. D., Zabaleta, N., Aldabe, R., & Gonzalez-Aseguinolaza, G. (2021). Novel vectors and approaches for gene therapy in liver diseases. JHEP Reports: Innovation in Hepatology, 3(4), 100300. https://doi.org/10.1016/j.jhepr.2021.100300

Matei, D., Buculei, I., Luca, C., Corciova, C. P., Andritoi, D., Fuior, R., Iordan, D. A., & Onu, I. (2022). Impact of non-pharmacological interventions on the mechanisms of atherosclerosis. International Journal of Molecular Sciences, 23(16), 9097. https://doi.org/10.3390/ijms23169097

Matthan, N. R., Solano-Aguilar, G., Meng, H., Lamon-Fava, S., Goldbaum, A., Walker, M. E., Jang, S., Lakshman, S., Molokin, A., Xie, Y., Beshah, E., Stanley, J., Urban, J. F., Jr, & Lichtenstein, A. H. (2018). The Ossabaw pig is a suitable translational model to evaluate dietary patterns and coronary artery disease risk. The Journal of Nutrition, 148(4), 542–551. https://doi.org/10.1093/jn/nxy002

Mehu, M., Narasimhulu, C. A., & Singla, D. K. (2022). Inflammatory cells in atherosclerosis. Antioxidants (Basel, Switzerland), 11(2), 233. https://doi.org/10.3390/antiox11020233

Mughal, M. M., Khan, M. K., DeMarco, J. K., Majid, A., Shamoun, F., & Abela, G. S. (2011). Symptomatic and asymptomatic carotid artery plaque. Expert Review of Cardiovascular Therapy, 9(10), 1315–1330. https://doi.org/10.1586/erc.11.120

Mushenkova, N. V., Summerhill, V. I., Silaeva, Y. Y., Deykin, A. V., & Orekhov, A. N. (2019). Modelling of atherosclerosis in genetically modified animals. American Journal of Translational Research, 11(8), 4614–4633.

Nieswandt, B., & Schulte, V. (2022). Platelet function in animal models of atherosclerosis. Frontiers in Cardiovascular Medicine, 9, 829006. https://doi.org/10.3389/fcvm.2022.829006

Osborn, E. A., & Jaffer, F. A. (2013). Imaging atherosclerosis and risk of plaque rupture. Current Atherosclerosis Reports, 15(10), 359. https://doi.org/10.1007/s11883-013-0359-z

Papafaklis, M. I., Takahashi, S., Antoniadis, A. P., Coskun, A. U., Tsuda, M., Mizuno, S., Andreou, I., Nakamura, S., Makita, Y., Hirohata, A., Saito, S., Feldman, C. L., & Stone, P. H. (2015). Effect of the local hemodynamic environment on the de novo development and progression of eccentric coronary atherosclerosis in humans: Insights from PREDICTION. Atherosclerosis, 240(1), 205–211. https://doi.org/10.1016/j.atherosclerosis.2015.03.017

Phillips, K. A., Bales, K. L., Capitanio, J. P., Conley, A., Czoty, P. W., 't Hart, B. A., Hopkins, W. D., Hu, S. L., Miller, L. A., Nader, M. A., Nathanielsz, P. W., Rogers, J., Shively, C. A., & Voytko, M. L. (2014). Why primate models matter. American Journal of Primatology, 76(9), 801–827. https://doi.org/10.1002/ajp.22281

Poznyak, A. V., Silaeva, Y. Y., Orekhov, A. N., & Deykin, A. V. (2020). Animal models of human atherosclerosis: Current progress. Brazilian Journal of Medical and Biological Research, 53(6), e9557. https://doi.org/10.1590/1414-431x20209557

Rai, V., & Agrawal, D. K. (2017). The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques. Canadian Journal of Physiology and Pharmacology, 95(10), 1245–1253. https://doi.org/10.1139/cjpp-2016-0664

Rhoads, J. P., & Major, A. S. (2018). How oxidized low-density lipoprotein activates inflammatory responses. Critical Reviews in Immunology, 38(4), 333–342. https://doi.org/10.1615/CritRevImmunol.2018026483

Richardson, M., Gerrity, R. G., Alavi, M. Z., & Moore, S. (1982). Proteoglycan distribution in areas of differing permeability to Evans blue dye in the aortas of young pigs: An ultrastructural study. Arteriosclerosis (Dallas, Tex.), 2(5), 369–379. https://doi.org/10.1161/01.atv.2.5.369

Sarkar, S. K., Matyas, A., Asikhia, I., Hu, Z., Golder, M., Beehler, K., Kosenko, T., & Lagace, T. A. (2022). Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding. Frontiers in Physiology, 13, 960272. https://doi.org/10.3389/fphys.2022.960272

Somanathan, S., Jacobs, F., Wang, Q., Hanlon, A. L., Wilson, J. M., & Rader, D. J. (2014). AAV vectors expressing LDLR gain-of-function variants demonstrate increased efficacy in mouse models of familial hypercholesterolemia. Circulation Research, 115(6), 591–599. https://doi.org/10.1161/CIRCRESAHA.115.304008

Sorrentino, S. A., & Sobel, B. E. (2011). Myeloperoxidase: A link between inflammation and atherosclerosis. Circulation, 123(17), 1957–1959. https://doi.org/10.1161/CIRCULATIONAHA.111.039716

Spronk, H. M. H., Padro, T., Siland, J. E., Prochaska, J. H., Winters, J., van der Wal, A. C., Posthuma, J. J., Lowe, G., d'Alessandro, E., Wenzel, P., Coenen, D. M., Reitsma, P. H., Ruf, W., van Gorp, R. H., Koenen, R. R., Vajen, T., Alshaikh, N. A., Wolberg, A. S., Macrae, F. L., Asquith, N., … Ten Cate, H. (2018). Atherothrombosis and thromboembolism: Position paper from the Second Maastricht Consensus Conference on Thrombosis. Thrombosis and Haemostasis, 118(2), 229–250. https://doi.org/10.1160/TH17-07-0492

Stefanadis, C., Antoniou, C. K., Tsiachris, D., & Pietri, P. (2017). Coronary atherosclerotic vulnerable plaque: Current perspectives. Journal of the American Heart Association, 6(3), e005543. https://doi.org/10.1161/JAHA.117.005543

Storey, J., Gobbetti, T., Olzinski, A., & Berridge, B. R. (2021). A structured approach to optimizing animal model selection for human translation: The Animal Model Quality Assessment. ILAR Journal, 62(1-2), 66–76. https://doi.org/10.1093/ilar/ilac004

Swearengen, J. R. (2018). Choosing the right animal model for infectious disease research. Animal Models and Experimental Medicine, 1(2), 100–108. https://doi.org/10.1002/ame2.12020

Thim, T. (2010). Human-like atherosclerosis in minipigs: A new model for detection and treatment of vulnerable plaques. Danish Medical Bulletin, 57(7), B4161.

Tsang, H. G., Rashdan, N. A., Whitelaw, C. B., Corcoran, B. M., Summers, K. M., & MacRae, V. E. (2016). Large animal models of cardiovascular disease. Cell Biochemistry and Function, 34(3), 113–132. https://doi.org/10.1002/cbf.3173

Tsang, H. G., Rashdan, N. A., Whitelaw, C. B., Corcoran, B. M., Summers, K. M., & MacRae, V. E. (2016). Large animal models of cardiovascular disease. Cell Biochemistry and Function, 34(3), 113–132. https://doi.org/10.1002/cbf.3173

Tsimikas, S., & Miller, Y. I. (2020). Novel lipoprotein biomarkers for the prediction of cardiovascular risk: An update. Clinical Chemistry, 66(3), 440–453. https://doi.org/10.1373/clinchem.2019.319382

Vaseghi, G., Malakoutikhah, Z., Shafiee, Z., Gharipour, M., Shariati, L., Sadeghian, L., Khosravi, E., Javanmard, S. H., Pourmoghaddas, A., Laher, I., Zarfeshani, S., & Sarrafzadegan, N. (2021). Apolipoprotein B gene mutation related to familial hypercholesterolemia in an Iranian population: With or without hypothyroidism. Journal of Research in Medical Sciences: The Official Journal of Isfahan University of Medical Sciences, 26, 94. https://doi.org/10.4103/jrms.JRMS_970_19

Wang, D., Tai, P. W. L., & Gao, G. (2019). Adeno-associated virus vector as a platform for gene therapy delivery. Nature Reviews Drug Discovery, 18(5), 358–378. https://doi.org/10.1038/s41573-019-0012-9

Widhalm, K., Dirisamer, A., Lindemayr, A., & Kostner, G. (2007). Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations. Journal of Inherited Metabolic Disease, 30(2), 239–247. https://doi.org/10.1007/s10545-007-0563-5

Wilensky, R. L., Shi, Y., Mohler, E. R., 3rd, Hamamdzic, D., Burgert, M. E., Li, J., Postle, A., Fenning, R. S., Bollinger, J. G., Hoffman, B. E., Pelchovitz, D. J., Yang, J., Mirabile, R. C., Webb, C. L., Zhang, L., Zhang, P., Gelb, M. H., Walker, M. C., Zalewski, A., & Macphee, C. H. (2008). Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nature Medicine, 14(10), 1059–1066. https://doi.org/10.1038/nm.1870

Yuan, F., Guo, L., Park, K. H., Woollard, J. R., Taek-Geun, K., Jiang, K., Melkamu, T., Zang, B., Smith, S. L., Fahrenkrug, S. C., Kolodgie, F. D., Lerman, A., Virmani, R., Lerman, L. O., & Carlson, D. F. (2018). Ossabaw pigs with a PCSK9 gain-of-function mutation develop accelerated coronary atherosclerotic lesions: A novel model for preclinical studies. Journal of the American Heart Association, 7(6), e006207. https://doi.org/10.1161/JAHA.117.006207

Zhang, Y., Fatima, M., Hou, S., Bai, L., Zhao, S., & Liu, E. (2021). Research methods for animal models of atherosclerosis (Review). Molecular Medicine Reports, 24(6), 871. https://doi.org/10.3892/mmr.2021.12511

Zhao, L., Zhang, S., Su, Q., & Li, S. (2021). Effects of withdrawing an atherogenic diet on the atherosclerotic plaque in rabbits. Experimental and Therapeutic Medicine, 22(1), 751. https://doi.org/10.3892/etm.2021.10183

Zwicker, J. I., Trenor, C. C., 3rd, Furie, B. C., & Furie, B. (2011). Tissue factor-bearing microparticles and thrombus formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(4), 728–733. https://doi.org/10.1161/ATVBAHA.109.200964

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