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Article: Deletion of Rap1 protects against myocardial ischemia/reperfusion injury through suppressing cell apoptosis via activation of STAT3 signaling

TitleDeletion of Rap1 protects against myocardial ischemia/reperfusion injury through suppressing cell apoptosis via activation of STAT3 signaling
Authors
Keywordscardiomyocytes
ischemic heart disease
stattic
telomere
Issue Date2020
PublisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/
Citation
The FASEB Journal, 2020, v. 34 n. 3, p. 4482-4496 How to Cite?
AbstractIschemic heart disease is a leading cause of morbidity and mortality. Repressor activator protein 1 (Rap1), an established telomere-associated protein, is a novel modulator of hypoxia-induced apoptosis. This study aimed to explore the potential direct role of Rap1 in myocardial ischemia/reperfusion injury (I/RI) and to determine the underlying molecular mechanism. In a mouse model of myocardial I/RI (30-min of left descending coronary artery ligation followed by 2-h reperfusion), Rap1 deficiency significantly reduced myocardial infarct size (IS) and improved cardiac systolic/diastolic function. This was associated with a reduction in apoptosis in the post-ischemic myocardium. In H9C2 and primary cardiomyocytes, Rap1 knockdown or knockout significantly suppressed hypoxia/reoxygenation (H/R)-induced cell injury and apoptosis through increasing the phosphorylation/activation of STAT3 at site Ser727 and translocation of STAT3 to the nucleus. We surmise this since Stattic (selective STAT3 inhibitor) pretreatment canceled the abovementioned protective effect. Furthermore, co-immunoprecipitation assay revealed a direct interaction between Rap1 and STAT3, but not JAK2, suggesting that the association of Rap1 with STAT3 may contribute to the reduced activity of STAT3 (Ser727) upon H/R stimulation. In conclusion, Rap1 deficiency protects the heart from ischemic damage through STAT3-dependent reduction of cardiomyocyte apoptosis, which may yield viable target for pharmacological intervention in ischemic heart disease.
Persistent Identifierhttp://hdl.handle.net/10722/306484
ISSN
2023 Impact Factor: 4.4
2023 SCImago Journal Rankings: 1.412
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCai, Y-
dc.contributor.authorYing, F-
dc.contributor.authorLiu, H-
dc.contributor.authorGe, L-
dc.contributor.authorSong, E-
dc.contributor.authorWang, L-
dc.contributor.authorZhang, D-
dc.contributor.authorTang, EHC-
dc.contributor.authorXia, Z-
dc.contributor.authorIrwin, MG-
dc.date.accessioned2021-10-22T07:35:16Z-
dc.date.available2021-10-22T07:35:16Z-
dc.date.issued2020-
dc.identifier.citationThe FASEB Journal, 2020, v. 34 n. 3, p. 4482-4496-
dc.identifier.issn0892-6638-
dc.identifier.urihttp://hdl.handle.net/10722/306484-
dc.description.abstractIschemic heart disease is a leading cause of morbidity and mortality. Repressor activator protein 1 (Rap1), an established telomere-associated protein, is a novel modulator of hypoxia-induced apoptosis. This study aimed to explore the potential direct role of Rap1 in myocardial ischemia/reperfusion injury (I/RI) and to determine the underlying molecular mechanism. In a mouse model of myocardial I/RI (30-min of left descending coronary artery ligation followed by 2-h reperfusion), Rap1 deficiency significantly reduced myocardial infarct size (IS) and improved cardiac systolic/diastolic function. This was associated with a reduction in apoptosis in the post-ischemic myocardium. In H9C2 and primary cardiomyocytes, Rap1 knockdown or knockout significantly suppressed hypoxia/reoxygenation (H/R)-induced cell injury and apoptosis through increasing the phosphorylation/activation of STAT3 at site Ser727 and translocation of STAT3 to the nucleus. We surmise this since Stattic (selective STAT3 inhibitor) pretreatment canceled the abovementioned protective effect. Furthermore, co-immunoprecipitation assay revealed a direct interaction between Rap1 and STAT3, but not JAK2, suggesting that the association of Rap1 with STAT3 may contribute to the reduced activity of STAT3 (Ser727) upon H/R stimulation. In conclusion, Rap1 deficiency protects the heart from ischemic damage through STAT3-dependent reduction of cardiomyocyte apoptosis, which may yield viable target for pharmacological intervention in ischemic heart disease.-
dc.languageeng-
dc.publisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/-
dc.relation.ispartofThe FASEB Journal-
dc.rightsPreprint This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Postprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectcardiomyocytes-
dc.subjectischemic heart disease-
dc.subjectstattic-
dc.subjecttelomere-
dc.titleDeletion of Rap1 protects against myocardial ischemia/reperfusion injury through suppressing cell apoptosis via activation of STAT3 signaling-
dc.typeArticle-
dc.identifier.emailYing, F: sara130@hku.hk-
dc.identifier.emailXia, Z: zyxia@hku.hk-
dc.identifier.emailIrwin, MG: mgirwin@hku.hk-
dc.identifier.authorityXia, Z=rp00532-
dc.identifier.authorityIrwin, MG=rp00390-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1096/fj.201901592RR-
dc.identifier.pmid32020680-
dc.identifier.scopuseid_2-s2.0-85078953824-
dc.identifier.hkuros329038-
dc.identifier.volume34-
dc.identifier.issue3-
dc.identifier.spage4482-
dc.identifier.epage4496-
dc.identifier.isiWOS:000512308900001-
dc.publisher.placeUnited States-

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