{"id":1317,"date":"2026-04-06T13:42:27","date_gmt":"2026-04-06T13:42:27","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=1317"},"modified":"2026-09-30T13:55:45","modified_gmt":"2026-09-30T13:55:45","slug":"elementor-1317","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=1317","title":{"rendered":"Four LC types, four EP receptors?"},"content":{"rendered":"\t\t<div data-elementor-type=\"wp-page\" data-elementor-id=\"1317\" class=\"elementor elementor-1317\">\n\t\t\t\t<div class=\"elementor-element elementor-element-7a01636 e-flex e-con-boxed e-con e-parent\" data-id=\"7a01636\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-c08b2ec elementor-widget elementor-widget-heading\" data-id=\"c08b2ec\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"heading.default\">\n\t\t\t\t\t<h2 class=\"elementor-heading-title elementor-size-default\">Hypothetical EP receptor distribution in four subphenotypes of LC patients<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t<div class=\"elementor-element elementor-element-2a32d096 e-flex e-con-boxed e-con e-parent\" data-id=\"2a32d096\" data-element_type=\"container\" data-e-type=\"container\">\n\t\t\t\t\t<div class=\"e-con-inner\">\n\t\t\t\t<div class=\"elementor-element elementor-element-102ce156 elementor-widget elementor-widget-text-editor\" data-id=\"102ce156\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t<h2><\/h2>\n<p><a href=\"https:\/\/doi.org\/10.1038\/s41591-022-02116-3\">Zhang et al.<\/a> investigated the incidence and reproducibility of specific Long Covid-symptoms in individuals who contracted COVID19 (in the pre-Omicron period) <a href=\"#_ENREF_1\"><sup>1<\/sup><\/a>. In a development cohort of 20.881 and a validation cohort of 13.724 patients, they identified over 137 Long Covid symptoms and conditions in four reproducible subphenotypes <a href=\"#_ENREF_1\"><sup>1<\/sup><\/a>.<\/p>\n\n<ul class=\"wp-block-list\">\n<li>Type 1 \u201cCardiac and renal\u201d: Compared to the other subphenotypes patients were older, mean age 65 yrs, predominantly men, with more severe illness and the highest hospitalization rate. They also had the highest burden of comorbidities, ao cardiac and circulatory problemsand kidney problems<\/li>\n\n<li>Type 2 \u201cRespiratory, sleep and anxiety\u201d: consisted of more women, mean age 51 yrs.\u00a0<\/li>\n\n<li>Type 3 \u201cMusculoskeletal and nervous\u201d:more women and higher baseline comorbidity of autoimmune and allergy conditions, mean age 57 yrs.<\/li>\n\n<li>Type 4 \u201cDigestive and respiratory\u201d, smallest cohort, mainly female patients, digestive system, urinary and respiratory conditions, lower burden of underlying conditions, mean age 54 yrs.\u00a0<\/li>\n<\/ul>\n\n<p class=\"wp-block-paragraph\">We considered Zhang\u2019s data according to our \u2018EP receptor up and down\u2019 approach (Data-set 1.). We collected evidence that the symptoms of Zhangs \u201cType 1\u201d can be correlated with \u201cEP3 up\u201d. The symptoms of the other three types can be linked to \u201cEP3 down\u201d combined with \u201cEP1 up\u201d, \u201cEP2 up\u201d and \u201cEP4 up\u201d respectively (see for references Data-set 2).<br \/>Of significance:\u00a0 EP1, EP2 and EP4 are expected to upregulate by infections while EP3 expression is expected to downregulate, looking at the reported effect of PGE2\/COX-2 upregulation on EP receptor expressions (see full hypothesis article, section 3.1)<\/p>\n<p><strong>Data-set 1. Hypothetical EP receptor distribution in four <\/strong><strong>subphenotypes<\/strong><strong> of LC patients<\/strong><\/p>\n\n<figure class=\"wp-block-table\">\n<table class=\"has-fixed-layout\">\n<tbody>\n<tr>\n<td>Zhangs 4 types of Long COVID patients<\/td>\n<td>Characteristic LC subphenotypes<br \/>according to Zhangs research<br \/>and terminology<\/td>\n<td>Male\/female ratio<\/td>\n<td colspan=\"2\">Proposed distribution patterns of four EP expression based on our literature searches (see references in Data-set 1) compared with the presumed profiles of the other types and average EP expressions<\/td>\n<\/tr>\n<tr>\n<td><strong>Type 1<\/strong><\/td>\n<td>\u201cCardiac and renal\u201d<\/td>\n<td>\u00a0Mostly \u00a0male<\/td>\n<td>\n<p>EP3 up\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0<\/p>\n<\/td>\n<td><strong>\u00a0<\/strong><\/td>\n<\/tr>\n<tr>\n<td><strong>\u00a0<\/strong><strong>Type 2\u00a0<\/strong><\/td>\n<td>\u201cRespiratory, sleep<br \/>\u00a0and anxiety\u201d<\/td>\n<td>\u00a0Mostly female<\/td>\n<td>EP1 up<br \/>\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0<\/td>\n<td><strong>EP3 down<\/strong><\/td>\n<\/tr>\n<tr>\n<td><strong>Type 3<\/strong><\/td>\n<td>\u201cMusculoskeletal and nervous\u201d\u00a0<\/td>\n<td>\u00a0Mostly female<\/td>\n<td>EP2 up\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0<\/td>\n<td><strong>EP3 down<\/strong><\/td>\n<\/tr>\n<tr>\n<td><strong>Type 4<\/strong><\/td>\n<td>\u201cDigestive and respiratory\u201d<\/td>\n<td>\u00a0Mostly female<\/td>\n<td>EP4 up\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0<\/td>\n<td><strong>EP3 up\/down*<\/strong><\/td>\n<\/tr>\n<tr>\n<td colspan=\"5\">* EP4 expression (\u2191cAMP) up = EP3 capacity (\u2193cAMP) down, even when EP3 expression is up<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/figure>\n\n<p class=\"wp-block-paragraph\"><strong>Data-set 2. Four LC symptom clusters hypothetically associated with dominance of a distinct EP receptor<\/strong><\/p>\n\n<figure class=\"wp-block-table\">\n<table class=\"has-fixed-layout\">\n<tbody>\n<tr>\n<td>Type 1 \u201cCardiac and renal\u201d<br \/>EP3 up<br \/><br \/>PGE2-EP3 activity contributes to high blood pressure <a href=\"#_ENREF_2\"><sup>2<\/sup><\/a><sup>,<\/sup><a href=\"#_ENREF_3\"><sup>3<\/sup><\/a> and cardiac <a href=\"#_ENREF_4\"><sup>4-8<\/sup><\/a> and renal<br \/><a href=\"#_ENREF_9\"><sup>9-12<\/sup><\/a> problems<\/td>\n<td>\u00a0Type 4 \u201cDigestive and respiratory\u201d<br \/>\u00a0EP4 up<br \/><br \/>\u00a0PGE2-EP4 activity stimulates bile <a href=\"#_ENREF_13\"><sup>13<\/sup><\/a> and reportedly contributes to gastrointestinal <a href=\"#_ENREF_14\"><sup>14-16<\/sup><\/a> and airway <a href=\"#_ENREF_17\"><sup>17<\/sup><\/a><sup>,<\/sup><a href=\"#_ENREF_18\"><sup>18<\/sup><\/a> problems<br \/>\u2013 bile stimulates both <a href=\"#_ENREF_19\"><sup>19<\/sup><\/a><sup>,<\/sup><a href=\"#_ENREF_20\"><sup>20<\/sup><\/a>\u00a0<\/td>\n<\/tr>\n<tr>\n<td>Type 2\u00a0\u201cRespiratory, sleep and anxiety\u201d<br \/>EP1 up<br \/><br \/>PGE2-EP1 activity contributes to respiratory problems <a href=\"#_ENREF_21\"><sup>21-24<\/sup><\/a> and mediates elevated anxiety <a href=\"#_ENREF_25\"><sup>25<\/sup><\/a>. PGE2 and COX-2 derived PGD2 through EP1 have opposing roles in sleep regulation <a href=\"#_ENREF_26\"><sup>26<\/sup><\/a><\/td>\n<td>\u00a0Type 3 \u201cMusculoskeletal and nervous\u201d<br \/>\u00a0EP2 up<br \/><br \/>\u00a0PGE2-EP2 activity stimulates oligodendrocyte apoptosis and demyelination, possibly contributing to musculoskeletal <a href=\"#_ENREF_27\"><sup>27-30<\/sup><\/a><sup>,<\/sup><a href=\"#_ENREF_31\"><sup>31<\/sup><\/a> and nervous <a href=\"#_ENREF_32\"><sup>32-35<\/sup><\/a> problems. PGE2-EP2 stimulates aldosterone <a href=\"#_ENREF_36\"><sup>36<\/sup><\/a> and aldosterone upregulation is associated with damages to skeletal muscle cells <a href=\"#_ENREF_37\"><sup>37<\/sup><\/a><sup>,<\/sup><a href=\"#_ENREF_38\"><sup>38<\/sup><\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/figure>\n\n<p class=\"wp-block-paragraph\"><br \/>These models might help finding the right treatment for more specific types of Long COVID patients.<\/p>\n<hr class=\"wp-block-separator has-alpha-channel-opacity\" \/>\n<p class=\"wp-block-paragraph\">References<br \/><br \/><\/p>\n\n<p class=\"wp-block-paragraph\"><a id=\"_ENREF_1\"><\/a>1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Zhang, H.<em> et al.<\/em> Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes. <em>Nature Medicine<\/em> <strong>29<\/strong>, 226-235 (2023). <a href=\"https:\/\/doi.org\/10.1038\/s41591-022-02116-3\">https:\/\/doi.org\/10.1038\/s41591-022-02116-3<\/a><\/p>\n\n<p class=\"wp-block-paragraph\"><a id=\"_ENREF_2\"><\/a>2\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bryson, T.<em> et al.<\/em> The Deleterious Role of the Prostaglandin E 2 EP3 Receptor in Angiotensin II Hypertension. <em>American Journal of Physiology-Heart and Circulatory Physiology<\/em> <strong>318<\/strong> (2020). <a href=\"https:\/\/doi.org\/10.1152\/ajpheart.00538.2019\">https:\/\/doi.org\/10.1152\/ajpheart.00538.2019<\/a><\/p>\n\n<p class=\"wp-block-paragraph\"><a id=\"_ENREF_3\"><\/a>3\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Wu, J.<em> et al.<\/em> EP3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation in a Mouse Model of Salt-Sensitive Hypertension. <em>Hypertension<\/em> <strong>77<\/strong>, 1399-1411 (2021). <a href=\"https:\/\/doi.org\/doi:10.1161\/HYPERTENSIONAHA.120.16518\">https:\/\/doi.org\/doi:10.1161\/HYPERTENSIONAHA.120.16518<\/a><\/p>\n\n<p class=\"wp-block-paragraph\"><a id=\"_ENREF_4\"><\/a>4\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bryson, T. 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Shear-induced interleukin-6 synthesis in chondrocytes: roles of E prostanoid (EP) 2 and EP3 in cAMP\/protein kinase A- and PI3-K\/Akt-dependent NF-kappaB activation. <\/a><em>J Biol Chem<\/em> <strong>285<\/strong>, 24793-24804 (2010). <a href=\"https:\/\/doi.org\/10.1074\/jbc.M110.110320\">https:\/\/doi.org\/10.1074\/jbc.M110.110320<\/a><\/p>\n\n<p class=\"wp-block-paragraph\"><a>30\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Sato, T.<em> et al.<\/em> Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes. <\/a><em>Ann Rheum Dis<\/em> <strong>70<\/strong>, 221-226 (2011). <a href=\"https:\/\/doi.org\/10.1136\/ard.2009.118620\">https:\/\/doi.org\/10.1136\/ard.2009.118620<\/a><\/p>\n\n<p class=\"wp-block-paragraph\"><a id=\"_ENREF_31\"><\/a>31\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ota, H.<em> et al.<\/em> EP2 receptor plays pivotal roles in generating mechanical hyperalgesia after lengthening contractions. <em>Scand J Med Sci Sports<\/em> <strong>28<\/strong>, 826-833 (2018). <a href=\"https:\/\/doi.org\/10.1111\/sms.12954\">https:\/\/doi.org\/10.1111\/sms.12954<\/a><\/p>\n\n<p class=\"wp-block-paragraph\"><a id=\"_ENREF_32\"><\/a>32\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Lushington, R., Camilli, S., Pascual, F., Lockey, R. 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Extrarenal Effects of Aldosterone on Potassium Homeostasis. <em>Kidney360<\/em> <strong>3<\/strong>, 561-568 (2022). <a href=\"https:\/\/doi.org\/10.34067\/kid.0006762021\">https:\/\/doi.org\/10.34067\/kid.0006762021<\/a><\/p>\n\n<p class=\"wp-block-paragraph\">\u00a0<\/p>\n\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"<p>Hypothetical EP receptor distribution in four subphenotypes of LC patients We considered Zhang\u2019s data according to our \u2018EP receptor up [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"class_list":["post-1317","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/1317","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1317"}],"version-history":[{"count":35,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/1317\/revisions"}],"predecessor-version":[{"id":6736,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/1317\/revisions\/6736"}],"wp:attachment":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1317"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}