{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T08:13:43Z","timestamp":1772784823987,"version":"3.50.1"},"reference-count":102,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T00:00:00Z","timestamp":1554854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL101917 and HL062565 to ARR"],"award-info":[{"award-number":["HL101917 and HL062565 to ARR"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01HL051971 to JL"],"award-info":[{"award-number":["P01HL051971 to JL"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of APC have been extensively studied and confirmed in a number of preclinical disease and injury models including sepsis, type-1 diabetes and various ischemia\/reperfusion diseases. It is now well-known that APC modulates downstream cell signaling networks and transcriptome profiles when it binds to the endothelial protein C receptor (EPCR) to activate protease-activated receptor 1 (PAR1) on various cell types. However, despite much progress, details of the downstream signaling mechanism of APC and its crosstalk with other signaling networks are far from being fully understood. In this review, we focus on the cardioprotective properties of APC in ischemic heart disease and heart failure with a special emphasis on recent discoveries related to the modulatory effect of APC on AMP-activated protein kinase (AMPK), PI3K\/AKT, and mTORC1 signaling pathways. The cytoprotective properties of APC might provide a novel strategy for future therapies in cardiac diseases.<\/jats:p>","DOI":"10.3390\/ijms20071762","type":"journal-article","created":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T11:25:08Z","timestamp":1554895508000},"page":"1762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The Cardioprotective Signaling Activity of Activated Protein C in Heart Failure and Ischemic Heart Diseases"],"prefix":"10.3390","volume":"20","author":[{"given":"Di","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemant","family":"Giri","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0899-4412","authenticated-orcid":false,"given":"Ji","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5302-0553","authenticated-orcid":false,"given":"Alireza R.","family":"Rezaie","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"},{"name":"University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1182\/blood.V60.1.261.261","article-title":"Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation","volume":"60","author":"Griffin","year":"1982","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4766","DOI":"10.1073\/pnas.81.15.4766","article-title":"Characterization of a cDNA coding for human protein C","volume":"81","author":"Foster","year":"1984","journal-title":"Proc. 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