title: A soluble receptor for advanced glycation end-products inhibits myocardial apoptosis induced by ischemia/reperfusion via the JAK2/STAT3 pathway.
abstract: sRAGE can protect cardiomyocytes from apoptosis induced by ischemia/reperfusion (I/R). However, the signaling mechanisms in cardioprotection by sRAGE are currently unknown. We investigated the cardioprotective effect and potential molecular mechanisms of sRAGE inhibition on apoptosis in the mouse myocardial I/R as an in vivo model and neonatal rat cardiomyocyte subjected to ischemic buffer as an in vitro model. Cardiac function and myocardial infarct size following by I/R were evaluated with echocardiography and Evans blue/2,3,5-triphenyltetrazolium chloride. Apoptosis was detected by TUNEL staining and caspase-3 activity. Expression of the apoptosis-related proteins p53, Bax, Bcl-2, JAK2/p-JAK2, STAT3/p-STAT3, AKT/p-AKT, ERK/p-ERK, STAT5A/p-STAT5A and STAT6/p-STAT6 were detected by western blot analysis in the presence and absence of the JAK2 inhibitor AG 490. sRAGE (100 µg/day) improved the heart function in mice with I/R: the left ventricular ejection fraction and fractional shortening were increased by 42 and 57%, respectively; the infarct size was decreased by 52%, the TUNEL-positive myocytes by 66%, and activity of caspase-3 by 24%, the protein expression of p53 and ratio of Bax to Bcl-2 by 29 and 88%, respectively; protein expression of the p-JAK2, p-STAT3 and p-AKT were increased by 92, 280 and 31%, respectively. sRAGE have no effect on protein expression of p-ERK1/2, p-STAT5A and p-STAT6 following by I/R. sRAGE (900 nmol/L) exhibited anti-apoptotic effects in cardiomyocytes by decreasing TUNEL-positive myocytes by 67% and caspase-3 activity by 20%, p53 protein level and the Bax/Bcl-2 ratio by 58 and 86%, respectively; increasing protein expression of the p-JAK2 and p-STAT3 by 26 and 156%, respectively, p-AKT protein level by 33%. The anti-apoptotic effects of sRAGE following I/R were blocked by JAK2 inhibitor AG 490. The effect of sRAGE reduction on TUNEL-positive myocytes and caspase-3 activity were abolished by PI3K inhibitor LY294002, but not ERK 1/2 inhibitor PD98059. These results suggest that sRAGE protects cardiomyocytes from apoptosis induced by I/R in vitro and in vivo by activating the JAK2/STAT3 signaling pathway.
authors.affiliation: Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Jiang
authors.forename: Cai-xia
authors.initials: CX
authors.lastname: Guo
authors.forename: Xiang-jun
authors.initials: XJ
authors.lastname: Zeng
authors.forename: Hui-hua
authors.initials: HH
authors.lastname: Li
authors.forename: Bu-xing
authors.initials: BX
authors.lastname: Chen
authors.forename: Feng-he
authors.initials: FH
authors.lastname: Du
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D005419:Flavonoids; D009025:Morpholines; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C518603:protein kinase inhibitor peptide (5-24); C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one