Translational Animal Models in Drug Discovery and Development

Animal Models of Atherosclerosis and Spontaneous Plaque Rupture

Author(s): Andrew R. Bond and Christopher L. Jackson

Pp: 3-23 (21)

DOI: 10.2174/978160805469511201010003

* (Excluding Mailing and Handling)

Abstract

Atherosclerosis is a potentially fatal disease of the arteries affecting everyone, yet there are relatively few animal models that enable research into the events leading up to the rupture of an atherosclerotic plaque (the underlying cause of the majority of fatal thrombotic events). The apolipoprotein E knockout (ApoE-/-) mouse has been used for over a decade now, because when fed a high-fat diet it develops lesions in the brachiocephalic artery that spontaneously rupture at a known time point. Critics argue that the ApoE-/- mouse does not exactly replicate human atherosclerotic plaque rupture, yet this model gives us valuable insight into the mechanisms and processes leading up to this clinically significant event. In this article, atherosclerosis shall be discussed, followed by some examples of animal models of atherosclerosis and plaque rupture used before the development of the ApoE-/- mouse model. Differences between mice and humans, and also the reasons that the ApoE-/- mouse model is of great benefit to the field of atherosclerotic plaque rupture are discussed, followed by recent translational applications of the model.


Keywords: Animal model, apolipoprotein E, atherosclerosis, cardiovascular disease, drug discovery, drug development, mouse, plaque rupture, statin, thrombosis, translational model.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314349518 and j.to_ip >=314349518 )) and ((j.from_date <= 1740497790 and j.to_date >= 1740497790 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4522) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314349518 and j.to_ip >=314349518 )) and ((j.from_date <= 1740497790 and j.to_date >= 1740497790 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4522) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314349518 and j.to_ip >=314349518 )) and ((j.from_date <= 1740497790 and j.to_date >= 1740497790 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4522)
      690μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1119 and `b`.`banner_from_date` <= 1740497790 and `b`.`banner_to_date` >= 1740497790 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.51msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1119
      • 3: 1740497790
      • 4: 1740497790
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='c4df74b25905473816d2043e30432ef7'
      450μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    11Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        OhCd4PeGVVR2kTKdQ5bhl5e2inAJMZNOTBL7xqXx
        uc_cart_id
        c4df74b25905473816d2043e30432ef7
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/4522" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/4522
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IlM0UCt3OUpsV29sbWtxRnlEYWJmR1E9PSIsInZhbHVlIjoienZoSWpDVHNMSjhwS29sSDhaNEJNOU5Obnk2MGJOMGRVTjREWWVrdUpxND0iLCJtYWMiOiJkMmQ3OTRhNTBlOTE5ZjMzYWFlMmExNmYzNmI5YTZkNDk1ZTM3OGU3OTlmYjc4MTE4MmQzM2NlNzYzMjhiYjk4IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IlM0UCt3OUpsV29sbWtxRnlEYWJmR1E9PSIsInZhbHVlIjoienZoSWpDVHNMSjhwS29sSDhaNEJNOU5Obnk2MGJOMGRVTjREWWVrdUpxND0iLCJtYWMiOiJkMmQ3OTRhNTBlOTE5" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 15:36:30 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkZCQTMzbW9IRDhyT3NqbkNrTkFKOGc9PSIsInZhbHVlIjoibWNicTNsaEExRU96NUQwV1J4eWQ5dnhKckx6d0o4anBnNElSYW9xOFhzYzZEU1E0NXEzdEl2UU9GeGJ6Q2NRZmFiY0MrQnREcUpSaTZKbHQ4YVp4eVBpUGcwWjBmaWhPMk9tWDZ3UmpnVDJmQmJHSS9TU05XS2pzdnVoTmU0VDciLCJtYWMiOiIxYTFmYjc3NDJjNzRkODhmOTkyOWMyNzY5NTEwYzBlZWI1MDU5MDI0ZjdlZmVhZTI4YjU3YjFiMmVmYjRhMGQxIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:36:30 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IkZCQTMzbW9IRDhyT3NqbkNrTkFKOGc9PSIsInZhbHVlIjoibWNicTNsaEExRU96NUQwV1J4eWQ5dnhKckx6d0o4anBnNElSYW9xOFhzYzZEU1E0NXEzdEl2UU9GeGJ6Q2NRZmFiY0MrQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6Imc4YU5mcVFQQTBhUktHdzJKdnh1UWc9PSIsInZhbHVlIjoiV29mUlZIMndkQmd6eHpZZEVqSHlha25GUml2M2wxUnVVSlBMeE1VU1JCazd1aHZLalJTU216MFU0QnlnTFFMQy9Sc2o0WGJnU0FnK05vcE4xNVM2eG0zOWJCWHlHN0l3SHRDTW8yRUZrV1YwRGN4c0R3dXBsNTIza1NkY2hRRXUiLCJtYWMiOiJlNzFjYTQwMTQ3MjZlOTJkOTEyMmNhOGRmNDQzNjZiMjQyM2Q4Zjg2YTQzMjlmMTU3MjVlNmM1MWU1NDQzMGI0IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Imc4YU5mcVFQQTBhUktHdzJKdnh1UWc9PSIsInZhbHVlIjoiV29mUlZIMndkQmd6eHpZZEVqSHlha25GUml2M2wxUnVVSlBMeE1VU1JCazd1aHZLalJTU216MFU" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkZCQTMzbW9IRDhyT3NqbkNrTkFKOGc9PSIsInZhbHVlIjoibWNicTNsaEExRU96NUQwV1J4eWQ5dnhKckx6d0o4anBnNElSYW9xOFhzYzZEU1E0NXEzdEl2UU9GeGJ6Q2NRZmFiY0MrQnREcUpSaTZKbHQ4YVp4eVBpUGcwWjBmaWhPMk9tWDZ3UmpnVDJmQmJHSS9TU05XS2pzdnVoTmU0VDciLCJtYWMiOiIxYTFmYjc3NDJjNzRkODhmOTkyOWMyNzY5NTEwYzBlZWI1MDU5MDI0ZjdlZmVhZTI4YjU3YjFiMmVmYjRhMGQxIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:36:30 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IkZCQTMzbW9IRDhyT3NqbkNrTkFKOGc9PSIsInZhbHVlIjoibWNicTNsaEExRU96NUQwV1J4eWQ5dnhKckx6d0o4anBnNElSYW9xOFhzYzZEU1E0NXEzdEl2UU9GeGJ6Q2NRZmFiY0MrQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6Imc4YU5mcVFQQTBhUktHdzJKdnh1UWc9PSIsInZhbHVlIjoiV29mUlZIMndkQmd6eHpZZEVqSHlha25GUml2M2wxUnVVSlBMeE1VU1JCazd1aHZLalJTU216MFU0QnlnTFFMQy9Sc2o0WGJnU0FnK05vcE4xNVM2eG0zOWJCWHlHN0l3SHRDTW8yRUZrV1YwRGN4c0R3dXBsNTIza1NkY2hRRXUiLCJtYWMiOiJlNzFjYTQwMTQ3MjZlOTJkOTEyMmNhOGRmNDQzNjZiMjQyM2Q4Zjg2YTQzMjlmMTU3MjVlNmM1MWU1NDQzMGI0IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Imc4YU5mcVFQQTBhUktHdzJKdnh1UWc9PSIsInZhbHVlIjoiV29mUlZIMndkQmd6eHpZZEVqSHlha25GUml2M2wxUnVVSlBMeE1VU1JCazd1aHZLalJTU216MFU" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "OhCd4PeGVVR2kTKdQ5bhl5e2inAJMZNOTBL7xqXx" "uc_cart_id" => "c4df74b25905473816d2043e30432ef7" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/4522" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:36:30GET/chapter/45221121913