title: Beta-1-adrenergic receptors mediate Nrf2-HO-1-HMGB1 axis regulation to attenuate hypoxia/reoxygenation-induced cardiomyocytes injury in vitro.
abstract: BACKGROUD/AIMS: The aim of the study was to evaluate the effects of beta1-adrenergic receptors (β1-ARs) -mediated nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1)-high mobility group box 1 protein (HMGB1) axis regulation in hypoxia/reoxygenation (H/R)-induced neonatal rat cardiomyocytes.
  
  
  METHODS
  The neonatal cultured cardiomyocytes were concentration-dependently pretreated by dobutamine (DOB), a selective β1-adrenergic receptor agonist, in the absence and/or presence of LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor), SB203580 (a p38mitogen-activated-protein kinase (p38MAPK) inhibitor), Nrf2siRNA and HO-1siRNA, respectively, and then treated by H/R. The effects and mechanisms by which H/R-induced cardiomyocytes injury were evaluated.
  
  
  RESULTS
  Significant increase of HO-1 was found in neonatal cultured cardiomyocytes treated with DOB, when compared to the control group. Significant change for Nrf2 translocation was also revealed in neonatal cultured cardiomyocytes treated with DOB. Insignificant decreases of NF-kappaB p65 activation and HMGB1 release were observed in H/R-induced neonatal cultured cardiomyocytes treated with DOB, when compared to the control group. Importantly, DOB treatment significantly increased the cell viability and decreased the levels of LDH and MDA in H/R-induced cardiomyocytes injury. However, DOB failed to increase HO-1, inhibit NF-kappaB p65 activation, prevent HMGB1 release and attenuate H/R-induced cardiomyocytes injury when the cultured cardiomyocytes were pretreated by Nrf2siRNA, HO-1siRNA, PI3K inhibitor (LY294002) and p38MAPK inhibitor (SB203580), respectively.
  
  
  CONCLUSIONS
  β1-ARs-mediated Nrf2-HO-1-HMGB1 axis regulation plays a critical protective role in H/R-induced neonatal rat cardiomyocytes injury in vitro via PI3K/p38MAPK signaling pathway.
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, P. R. China.
authors: Jichun
authors: J
authors: Wang
authors: Xiaorong
authors: X
authors: Hu
authors: Jing
authors: J
authors: Xie
authors: Weipan
authors: W
authors: Xu
authors: Hong
authors: H
authors: Jiang
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D009025:Morpholines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*
chemical_list: C547789:Adrb1 protein, rat; D058665:Adrenergic beta-1 Receptor Agonists; D002867:Chromones; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D007093:Imidazoles; D009025:Morpholines; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011725:Pyridines; D018342:Receptors, Adrenergic, beta-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004280:Dobutamine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C093642:SB 203580