Sohel Shamsuzzaman, Rebecca A Deaton, Anita Salamon, Heather Doviak, Vlad Serbulea, Victoria M Milosek, Megan A Evans, Santosh Karnewar, Subhi Saibaba, Gabriel F Alencar, Laura S Shankman, Kenneth Walsh, Stefan Bekiranov, Olivier Kocher, Monty Krieger, Bengt Kull, Marie Persson, Erik Michaëlsson, Nils Bergenhem, Sepideh Heydarkhan-Hagvall, Gary K Owens
{"title":"心肌梗塞、斑块破裂和中风的新型小鼠模型显示,髓过氧化物酶抑制剂可改善存活率。","authors":"Sohel Shamsuzzaman, Rebecca A Deaton, Anita Salamon, Heather Doviak, Vlad Serbulea, Victoria M Milosek, Megan A Evans, Santosh Karnewar, Subhi Saibaba, Gabriel F Alencar, Laura S Shankman, Kenneth Walsh, Stefan Bekiranov, Olivier Kocher, Monty Krieger, Bengt Kull, Marie Persson, Erik Michaëlsson, Nils Bergenhem, Sepideh Heydarkhan-Hagvall, Gary K Owens","doi":"10.1161/CIRCULATIONAHA.123.067931","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke.</p><p><strong>Methods: </strong>We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with <i>Ldlr</i> knockout (designated SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup>). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions.</p><p><strong>Results: </strong>SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions.</p><p><strong>Conclusions: </strong>WD-fed SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347105/pdf/","citationCount":"0","resultStr":"{\"title\":\"Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition.\",\"authors\":\"Sohel Shamsuzzaman, Rebecca A Deaton, Anita Salamon, Heather Doviak, Vlad Serbulea, Victoria M Milosek, Megan A Evans, Santosh Karnewar, Subhi Saibaba, Gabriel F Alencar, Laura S Shankman, Kenneth Walsh, Stefan Bekiranov, Olivier Kocher, Monty Krieger, Bengt Kull, Marie Persson, Erik Michaëlsson, Nils Bergenhem, Sepideh Heydarkhan-Hagvall, Gary K Owens\",\"doi\":\"10.1161/CIRCULATIONAHA.123.067931\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke.</p><p><strong>Methods: </strong>We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with <i>Ldlr</i> knockout (designated SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup>). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions.</p><p><strong>Results: </strong>SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions.</p><p><strong>Conclusions: </strong>WD-fed SR-BI<sup>∆CT/∆CT</sup>/<i>Ldlr</i><sup><i>-/-</i></sup> mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.</p>\",\"PeriodicalId\":10331,\"journal\":{\"name\":\"Circulation\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":35.5000,\"publicationDate\":\"2024-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347105/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCULATIONAHA.123.067931\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/17 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.123.067931","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/17 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition.
Background: Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke.
Methods: We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with Ldlr knockout (designated SR-BI∆CT/∆CT/Ldlr-/-). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI∆CT/∆CT/Ldlr-/- mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions.
Results: SR-BI∆CT/∆CT/Ldlr-/- mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions.
Conclusions: WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.
期刊介绍:
Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.