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

Autor: Kota Okabe, Kazutoshi Mawatari, Hideo Yasukawa, Jinya Takahashi, Mai Yamamoto, T Sasaki, Shoichiro Nohara, Koutatsu Shimozono, Toshiyuki Yanai, Yoshihiro Fukumoto, Takanobu Nagata, Daiki Akagaki, Tatsuhiro Shibata
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cell signaling
Physiology
medicine.medical_treatment
Artificial Gene Amplification and Extension
030204 cardiovascular system & hematology
Pharmacology
Signal transduction
Vascular Medicine
Polymerase Chain Reaction
Mice
0302 clinical medicine
Ischemia
Immune Physiology
Medicine and Health Sciences
Medicine
Myocytes
Cardiac
SOCS3
Myocardial infarction
Ischemic Preconditioning
Cardioprotection
Mice
Knockout
Innate Immune System
Multidisciplinary
Genetically Modified Organisms
digestive
oral
and skin physiology
Heart
Animal Models
STAT signaling
Cytokine
Experimental Organism Systems
Cytokines
Engineering and Technology
Anatomy
Genetic Engineering
medicine.drug
Research Article
Biotechnology
Cell biology
Science
Immunology
Myocardial Reperfusion Injury
Mouse Models
Bioengineering
Research and Analysis Methods
03 medical and health sciences
Model Organisms
Animals
cardiovascular diseases
Molecular Biology Techniques
Erythropoietin
Molecular Biology
Genetically Modified Animals
business.industry
Biology and Life Sciences
Molecular Development
medicine.disease
030104 developmental biology
Suppressor of Cytokine Signaling 3 Protein
Immune System
Reperfusion
Cardiovascular Anatomy
Animal Studies
Ischemic preconditioning
business
Physiological Processes
Reperfusion injury
Developmental Biology
Zdroj: PLoS ONE, Vol 16, Iss 7, p e0254712 (2021)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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