SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.

Ischemic preconditioning (IPC) is the most powerful endogenous cardioprotective form of cellular adaptation. However, the inhibitory or augmenting mechanism underlying cardioprotection via IPC remains largely unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative...

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Autores principales:	Shoichiro Nohara, Mai Yamamoto, Hideo Yasukawa, Takanobu Nagata, Jinya Takahashi, Koutatsu Shimozono, Toshiyuki Yanai, Tomoko Sasaki, Kota Okabe, Tatsuhiro Shibata, Daiki Akagaki, Kazutoshi Mawatari, Yoshihiro Fukumoto
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4f80687e6dd540a3a793ca38f9088e8e
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spelling	oai:doaj.org-article:4f80687e6dd540a3a793ca38f9088e8e2021-12-02T20:06:39ZSOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.1932-620310.1371/journal.pone.0254712https://doaj.org/article/4f80687e6dd540a3a793ca38f9088e8e2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254712https://doaj.org/toc/1932-6203Ischemic preconditioning (IPC) is the most powerful endogenous cardioprotective form of cellular adaptation. However, the inhibitory or augmenting mechanism underlying cardioprotection via IPC remains largely unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative feedback regulator of the signal transducer and activator of transcription-3 (STAT3) signaling pathway. Here, we aimed to determine whether cardiac SOCS3 deficiency and IPC would synergistically reduce infarct size after myocardial ischemia reperfusion injury. We evaluated STAT3 activation and SOCS3 induction after ischemic conditioning (IC) using western blot analysis and real-time PCR, and found that myocardial IC alone transiently activated myocardial STAT3 and correspondingly induced SOCS3 expression in wild-type mice. Compared with wild-type mice, cardiac-specific SOCS3 knockout (SOCS3-CKO) mice showed significantly greater and more sustained IC-induced STAT3 activation. Following ischemia reperfusion, IPC substantially reduced myocardial infarct size and significantly enhanced STAT3 phosphorylation in SOCS3-CKO mice compared to in wild-type mice. Real-time PCR array analysis revealed that SOCS3-CKO mice after IC exhibited significantly increased expressions of several anti-apoptotic genes and SAFE pathway-related genes. Moreover, real-time PCR analysis revealed that myocardial IC alone rapidly induced expression of the STAT3-activating cytokine erythropoietin in the kidney at 1 h post-IC. We also found that the circulating erythropoietin level was promptly increased at 1 h after myocardial IC. Myocardial SOCS3 deficiency and IPC exert synergistic effects in the prevention of myocardial injury after ischemia reperfusion. Our present results suggest that myocardial SOCS3 is a potent inhibitor of IPC-induced cardioprotection, and that myocardial SOCS3 inhibition augment IPC-mediated cardioprotection during ischemia reperfusion injury.Shoichiro NoharaMai YamamotoHideo YasukawaTakanobu NagataJinya TakahashiKoutatsu ShimozonoToshiyuki YanaiTomoko SasakiKota OkabeTatsuhiro ShibataDaiki AkagakiKazutoshi MawatariYoshihiro FukumotoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254712 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shoichiro Nohara Mai Yamamoto Hideo Yasukawa Takanobu Nagata Jinya Takahashi Koutatsu Shimozono Toshiyuki Yanai Tomoko Sasaki Kota Okabe Tatsuhiro Shibata Daiki Akagaki Kazutoshi Mawatari Yoshihiro Fukumoto SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
description	Ischemic preconditioning (IPC) is the most powerful endogenous cardioprotective form of cellular adaptation. However, the inhibitory or augmenting mechanism underlying cardioprotection via IPC remains largely unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative feedback regulator of the signal transducer and activator of transcription-3 (STAT3) signaling pathway. Here, we aimed to determine whether cardiac SOCS3 deficiency and IPC would synergistically reduce infarct size after myocardial ischemia reperfusion injury. We evaluated STAT3 activation and SOCS3 induction after ischemic conditioning (IC) using western blot analysis and real-time PCR, and found that myocardial IC alone transiently activated myocardial STAT3 and correspondingly induced SOCS3 expression in wild-type mice. Compared with wild-type mice, cardiac-specific SOCS3 knockout (SOCS3-CKO) mice showed significantly greater and more sustained IC-induced STAT3 activation. Following ischemia reperfusion, IPC substantially reduced myocardial infarct size and significantly enhanced STAT3 phosphorylation in SOCS3-CKO mice compared to in wild-type mice. Real-time PCR array analysis revealed that SOCS3-CKO mice after IC exhibited significantly increased expressions of several anti-apoptotic genes and SAFE pathway-related genes. Moreover, real-time PCR analysis revealed that myocardial IC alone rapidly induced expression of the STAT3-activating cytokine erythropoietin in the kidney at 1 h post-IC. We also found that the circulating erythropoietin level was promptly increased at 1 h after myocardial IC. Myocardial SOCS3 deficiency and IPC exert synergistic effects in the prevention of myocardial injury after ischemia reperfusion. Our present results suggest that myocardial SOCS3 is a potent inhibitor of IPC-induced cardioprotection, and that myocardial SOCS3 inhibition augment IPC-mediated cardioprotection during ischemia reperfusion injury.
format	article
author	Shoichiro Nohara Mai Yamamoto Hideo Yasukawa Takanobu Nagata Jinya Takahashi Koutatsu Shimozono Toshiyuki Yanai Tomoko Sasaki Kota Okabe Tatsuhiro Shibata Daiki Akagaki Kazutoshi Mawatari Yoshihiro Fukumoto
author_facet	Shoichiro Nohara Mai Yamamoto Hideo Yasukawa Takanobu Nagata Jinya Takahashi Koutatsu Shimozono Toshiyuki Yanai Tomoko Sasaki Kota Okabe Tatsuhiro Shibata Daiki Akagaki Kazutoshi Mawatari Yoshihiro Fukumoto
author_sort	Shoichiro Nohara
title	SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
title_short	SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
title_full	SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
title_fullStr	SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
title_full_unstemmed	SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
title_sort	socs3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/4f80687e6dd540a3a793ca38f9088e8e
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SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.

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