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Conference Paper: Rap1 exacerbates myocardial ischemia/reperfusion injury through enhancing cell apoptosis and inflammatory response

TitleRap1 exacerbates myocardial ischemia/reperfusion injury through enhancing cell apoptosis and inflammatory response
Authors
Issue Date2018
PublisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/
Citation
Annual Meeting of Amer-Assoc-of-Anatomists (AAA), Amer-Physiol-Soc (APS), Amer-Soc-for-Biochemistry-and-Mol-Biol (ASBMB), Amer-Soc-for-Investigat-Pathol (ASIP), Amer-Soc-for-Pharmacol-and-Experimental-Therapeut (ASPET) on Experimental Biology (EB), San Diego, CA, 21-25 April 2018. In The FASEB Journal, 2018, v. 32 n. 1, suppl., abstract no. 698.12 How to Cite?
AbstractIschemic heart disease caused by partial or complete blockage of coronary arteries is a leading cause for morbidity and mortality worldwide. Repressor activator protein 1 (Rap1), an established telomere-associated protein, is a novel modulator in hypoxia-induced apoptosis and NFκB-mediated inflammatory response, both of which are involved in the pathophysiology of myocardial ischemia/reperfusion injury (I/RI). Thus, the present study aimed to explore whether or not Rap1 mediates cardiac I/RI in cell and animal models and to dissect its molecular mechanism. In a mice cardiac I/RI model (30 min left descending coronary artery ligation followed by 2 hours reperfusion), the protein expression of Rap1 in the heart was significantly increased (P <0.05 vs. Sham group). Deletion of Rap1 in mice significantly attenuated myocardial I/RI, as evidenced by reduced infarction size (Evans blue/TTC staining), reduced circulating levels of troponin I and creatine phosphokinase-MB (cardiac injury markers, P <0.05 vs. Wild-type mice). These changes were associated with reduced apoptosis (increased Bcl2/Bax ratio, reduced cleave caspase-3 level and TUNEL staining) and inflammatory responses [reduced mRNA levels of pro-inflammatory cytokines (IL1β, IL6 and TNFα) and infiltration of F4/80 positive cells (macrophage specific marker)] in the ischemic heart of Rap1 knockout mice (P<0.05 vs. Wild-type mice). In H9C2 cardiomyocytes, hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 12 hours reoxygenation) significantly increased both mRNA and protein levels of Rap1 (P <0.05 vs. Control). Rap1 knockdown significantly suppressed H/R-induced cell injury [reduced lactic acid dehydrogenase (LDH) leakage and increased cell viability] when compared to mock-transfected H9C2 cardiomyocytes. In addition, Rap1 knockdown significantly suppressed cell apoptosis in response to H/R (increased Bcl2/Bax ratio, reduced cleave caspase-3 level and TUNEL staining) through its ability to increase the phosphorylation/activation of STAT3 at site Ser727, as stattic (selective STAT3 inhibitor) pre-treatment canceled the abovementioned protective effect mediated by Rap1 knockdown. In line with this, Rap1 deficiency in mice also significantly increased the protein levels of p-STAT3 (Ser727) in the ischemic heart (P <0.05 vs. Wild-type mice). Furthermore, in differentiated THP-1 macrophages, Rap1 knockdown significantly suppressed lipopolysaccharide-induced expression of NFκB-mediated pro-inflammatory cytokines (IL1β, IL8 and MCP1). However, Rap1 knockdown did not influence the expression of NFκB-dependent targets in H/R-stimulated H9C2 cells, suggesting that the effect of Rap1 on NFκB-mediated inflammatory response is specific to macrophages. In conclusion, these data indicated that Rap1 can exacerbate myocardial I/RI through enhancing cell apoptosis via inhibiting STAT3 signaling in cardiomyocytes and also augmenting inflammatory response via up-regulation of macrophages infiltration and pro-inflammatory mediators. Thus, Rap1 may represent a novel therapeutic target for myocardial I/RI.
DescriptionExperimental Biology 2018 Meeting Abstract
Persistent Identifierhttp://hdl.handle.net/10722/272818
ISSN
2023 Impact Factor: 4.4
2023 SCImago Journal Rankings: 1.412
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCai, Y-
dc.contributor.authorIrwin, MG-
dc.contributor.authorXia, Z-
dc.date.accessioned2019-08-06T09:17:08Z-
dc.date.available2019-08-06T09:17:08Z-
dc.date.issued2018-
dc.identifier.citationAnnual Meeting of Amer-Assoc-of-Anatomists (AAA), Amer-Physiol-Soc (APS), Amer-Soc-for-Biochemistry-and-Mol-Biol (ASBMB), Amer-Soc-for-Investigat-Pathol (ASIP), Amer-Soc-for-Pharmacol-and-Experimental-Therapeut (ASPET) on Experimental Biology (EB), San Diego, CA, 21-25 April 2018. In The FASEB Journal, 2018, v. 32 n. 1, suppl., abstract no. 698.12-
dc.identifier.issn0892-6638-
dc.identifier.urihttp://hdl.handle.net/10722/272818-
dc.descriptionExperimental Biology 2018 Meeting Abstract-
dc.description.abstractIschemic heart disease caused by partial or complete blockage of coronary arteries is a leading cause for morbidity and mortality worldwide. Repressor activator protein 1 (Rap1), an established telomere-associated protein, is a novel modulator in hypoxia-induced apoptosis and NFκB-mediated inflammatory response, both of which are involved in the pathophysiology of myocardial ischemia/reperfusion injury (I/RI). Thus, the present study aimed to explore whether or not Rap1 mediates cardiac I/RI in cell and animal models and to dissect its molecular mechanism. In a mice cardiac I/RI model (30 min left descending coronary artery ligation followed by 2 hours reperfusion), the protein expression of Rap1 in the heart was significantly increased (P <0.05 vs. Sham group). Deletion of Rap1 in mice significantly attenuated myocardial I/RI, as evidenced by reduced infarction size (Evans blue/TTC staining), reduced circulating levels of troponin I and creatine phosphokinase-MB (cardiac injury markers, P <0.05 vs. Wild-type mice). These changes were associated with reduced apoptosis (increased Bcl2/Bax ratio, reduced cleave caspase-3 level and TUNEL staining) and inflammatory responses [reduced mRNA levels of pro-inflammatory cytokines (IL1β, IL6 and TNFα) and infiltration of F4/80 positive cells (macrophage specific marker)] in the ischemic heart of Rap1 knockout mice (P<0.05 vs. Wild-type mice). In H9C2 cardiomyocytes, hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 12 hours reoxygenation) significantly increased both mRNA and protein levels of Rap1 (P <0.05 vs. Control). Rap1 knockdown significantly suppressed H/R-induced cell injury [reduced lactic acid dehydrogenase (LDH) leakage and increased cell viability] when compared to mock-transfected H9C2 cardiomyocytes. In addition, Rap1 knockdown significantly suppressed cell apoptosis in response to H/R (increased Bcl2/Bax ratio, reduced cleave caspase-3 level and TUNEL staining) through its ability to increase the phosphorylation/activation of STAT3 at site Ser727, as stattic (selective STAT3 inhibitor) pre-treatment canceled the abovementioned protective effect mediated by Rap1 knockdown. In line with this, Rap1 deficiency in mice also significantly increased the protein levels of p-STAT3 (Ser727) in the ischemic heart (P <0.05 vs. Wild-type mice). Furthermore, in differentiated THP-1 macrophages, Rap1 knockdown significantly suppressed lipopolysaccharide-induced expression of NFκB-mediated pro-inflammatory cytokines (IL1β, IL8 and MCP1). However, Rap1 knockdown did not influence the expression of NFκB-dependent targets in H/R-stimulated H9C2 cells, suggesting that the effect of Rap1 on NFκB-mediated inflammatory response is specific to macrophages. In conclusion, these data indicated that Rap1 can exacerbate myocardial I/RI through enhancing cell apoptosis via inhibiting STAT3 signaling in cardiomyocytes and also augmenting inflammatory response via up-regulation of macrophages infiltration and pro-inflammatory mediators. Thus, Rap1 may represent a novel therapeutic target for myocardial I/RI.-
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.relation.ispartofExperimental Biology 2018 Meeting-
dc.titleRap1 exacerbates myocardial ischemia/reperfusion injury through enhancing cell apoptosis and inflammatory response-
dc.typeConference_Paper-
dc.identifier.emailCai, Y: caidavid@hku.hk-
dc.identifier.emailIrwin, MG: mgirwin@hku.hk-
dc.identifier.emailXia, Z: zyxia@hkucc.hku.hk-
dc.identifier.authorityIrwin, MG=rp00390-
dc.identifier.authorityXia, Z=rp00532-
dc.description.natureabstract-
dc.identifier.doi10.1096/fasebj.2018.32.1_supplement.698.12-
dc.identifier.hkuros299986-
dc.identifier.hkuros295391-
dc.identifier.volume32-
dc.identifier.issue1, suppl.-
dc.identifier.spageabstract no. 698.12-
dc.identifier.epageabstract no. 698.12-
dc.identifier.isiWOS:000436985005425-
dc.publisher.placeUnited States-
dc.identifier.issnl0892-6638-

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