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Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo\u2019s cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3\u2019s impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200\u2013380\u00a0g), buffer-perfused and subjected to 30\u00a0min\/120\u00a0min global zero-flow ischemia\/reperfusion (I\/R). In additional hearts, either iPoCo (2\u2009\u00d7\u200930\u00a0s\/30\u00a0s I\/R) was performed or T3 (100\u2013500\u00a0\u00b5g\/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16\u2009\u00b1\u20097% vs. 36\u2009\u00b1\u20094% with I\/R only. The maximum infarct size reduction was observed with 300\u00a0\u00b5g\/L T3 (14\u2009\u00b1\u20092%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1\/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3\u2019s cardioprotection (35\u2009\u00b1\u200910%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30\u00a0min\/5\u00a0min hypoxia\/reoxygenation (H\/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500\u00a0\u00b5g\/L T3 after H\/R (27\u2009\u00b1\u20094% of all cells vs. 5\u2009\u00b1\u20093% in time-matched controls). Again, RISK-BL abrogated protection (11\u2009\u00b1\u20093%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300\u00a0\u00b5g\/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3\u2019s protection is a cardiomyocyte phenomenon and targets mitochondria.<\/jats:p>","DOI":"10.1007\/s00395-021-00868-6","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T19:06:05Z","timestamp":1618859165000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes"],"prefix":"10.1007","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8631-3355","authenticated-orcid":false,"given":"Helmut Raphael","family":"Lieder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5929-052X","authenticated-orcid":false,"given":"Felix","family":"Braczko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilg\u00fcn","family":"Gedik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merlin","family":"Stroetges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7078-4160","authenticated-orcid":false,"given":"Gerd","family":"Heusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3576-3772","authenticated-orcid":false,"given":"Petra","family":"Kleinbongard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"868_CR1","doi-asserted-by":"publisher","first-page":"18558","DOI":"10.1074\/jbc.C500089200","volume":"280","author":"E Basso","year":"2005","unstructured":"Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of cyclophilin d. 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