Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex
Authors: Sheng-Hua Wu
Yu Zhou
Xiao-Qing Chen
Yan-Rong Tang
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: Lipoxin A4; heme oxygenase-1; cardiomyocytes; hypoxia/reoxygenation injury; Nrf2
Affiliations: Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

Abstract:  Objective: To investigate whether lipoxin A4 (LXA4) increases expression of heme oxygenase-1(HO-1) in cardiomyocytes, whether LXA4-induced HO-1 protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury, and what are the mechanisms involved in the LXA4-induced HO-1 induction. Methods: Rat cardiomyocytes were exposed to H/R injury with or without preincubation with LXA4 or HO-1 inhibitor ZnPP-IX or various signal molecule inhibitors. Expressions of HO-1 protein and mRNA were analyzed by using Western blot and RT-PCR respectively. Activity of nuclear factor E2-related factor 2 (Nrf2) binding to the HO-1 E1 enhancer was assessed by chromatin immunoprecipitation. Nrf2 binding to the HO-1 antioxidant responsive element (ARE) were measured by using electrophoretic mobility shift assay. Results: Pretreatment of the cells undergoing H/R lesion with LXA4 significantly reduced the lactate dehydrogenase and creatine kinase productions, increased the cell viability, and increased the expressions of HO-1 protein and mRNA and HO-1 promoter activity. HO-1 inhibition abolished the protective role of LXA4 on the cells undergoing H/R lesion. LXA4 increased p38 mitogen-activated protein kinase (p38 MAPK) activation, nuclear translocation of Nrf2, Nrf2 binding to the HO-1 ARE and E1 enhancer in cardiomyocytes with or without H/R exposure. Conclusion: The protection role of LXA4 against H/R injury of cardiomyocytes is related to upregulation of HO-1, via activation of p38 MAPK pathway and nuclear translocation of Nrf2 and Nrf2 binding to the HO-1 ARE and E1 enhancer, but not via activation of phosphatidyinositol-3-kinase or extracellular signal-regulated kinase pathway. 

Retracted: No

PubPeer comments:
 Fig 2(b).  Resibufogenin triggers apoptosis of SKOV3 and OVCAR-2 cells. SKOV3 and OVCAR-2 cells treated with resibufogenin (0, 2, and 5 u03bcM) for 48 h. Cell apoptosis was detected by ... b flow cytometry . ![file] Cf. 3B from [Liu Yu (2018)] : ![] Also [Dou et al (2019)] , and [below] 2A from [Wang et al (2018)] . ![] , 
  Fig. 3 Resibufogenin suppresses tumor growth in vivo. ... c The expression of apoptotic marker proteins cleaved caspase-3, Bcl-2, and Bax was examined by IHC . Also fig 5(c)  The expression of PIM1 in xenograft tissue was examined by IHC . Tumor panels are re-used from [Fig 7F of Pan et al (2018)] , though with different labels. I have left two panels uncolored as an exercise for the reader. ![] , 
 29 May 2020 Editoru2019s Note: The Editor in Chief is currently investigating this article as concerns have been raised regarding the integrity of some of data presented here. Further editorial action will be taken as appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full. , 
 Retracted [26 November 2020] ------------------------------------------------------- The Editor in Chief retracted this article (1) because of significant concerns regarding a number of Figures presented in this work, which question the integrity of the data. Specifically: Figure 2B contains images that appear to be the same or nearly the same as those published previously in a number of unrelated publications (2, 3, 4 - now retracted). Figure 3C and 5C contains a number of histopathology images which appear to have been previously published (5 - now retracted). The authors were unable to provide raw data. Author Ping Mo agreed to retraction but has not stated if they agree to this retraction notice. The remaining authors did not respond to any correspondence from the editor or publisher about this retraction. References - Bo L, Shou Y (2018) Amentoflavone suppresses hepatocellu-lar carcinoma by repressing hexokinase 2 expression through inhibiting JAK2 STAT3 signaling. Biomed Pharmacother 107:243u2013253. - Li Q, Jiang C, Wang Y (2019) Resibufogenin suppresses tumor growth and inhibits glycolysis in ovarian cancer by modulating PIM1. Naunyn-Schmiedeberg s Arch Pharmacol 392:1477u20131489. https: doi.org 10.1007 s00210-019-01687-2 - Qiang W, Yi Yan J, Zhang P, Guo Yuqing X, Yong W, Fawei Q, Qingyun Z (2018) Physcion 8-O-u03b2-glucopyranoside inhibits clear-cell renal cell carcinoma bydownregulating hexokinase II and inhibiting glycolysis. Biomed Pharmacother 104:28u201335. - Xiangyang D, Meihua W, Tao Z, Jiapei Y (2019) Physcion 8u2010Ou2010u03b2u2010glucopyranoside inhibits testicular germ cell tumors through regulating microRNAu2010199a. Anat Rec. https: doi.org 10.1002 ar.24324 - Xiaoping P, Chen W, Yan L, Lida Z, Ti Z (2018) Protective autophagy induced by physcion suppresses hepato-cellular carcinoma cell metastasis by inactivating the JAK2 STAT3 Axis. Life Sci 214:124u2013135. ,