title: Propofol mediates signal transducer and activator of transcription 3 activation and crosstalk with phosphoinositide 3-kinase/AKT.
abstract: We previously demonstrated that propofol, an intravenous anesthetic with anti-oxidative properties, activated the phosphoinositide 3-kinase (PI3K)/AKT pathway to increase the expression of B cell lymphoma (Bcl)-2 and, therefore the anti-apoptotic potential on cardiomyocytes. Here, we wanted to determine if propofol can also activate the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway, another branch of cardioprotective signaling. The cellular response of nuclear factor kappa B (NFκB) and STAT3 was also evaluated. Cardiac H9c2 cells were treated by propofol alone or in combination with pretreatment by inhibitors for JAK2/STAT3 or PI3K/AKT pathway. STAT3 and AKT phosphorylation, and STAT3 translocation were measured by western blotting and immunofluorescence staining, respectively. Propofol treatment significantly increased STAT3 phosphorylation at both tyrosine 705 and serine 727 residues. Sustained early phosphorylation of STAT3 was observed with 25~75 μM propofol at 10 and 30 min. Nuclear translocation of STAT3 was seen at 4 h after treatment with 50 μM propofol. In cultured H9c2 cells, we further demonstrated that propofol-induced STAT3 phosphorylation was reduced by pretreatment with PI3K/AKT pathway inhibitors wortmannin or API-2. Conversely, pretreatment with JAK2/STAT3 pathway inhibitor AG490 or stattic inhibited propofol-induced AKT phosphorylation. In addition, propofol induced NFκB p65 subunit perinuclear translocation. Inhibition or knockdown of STAT3 was associated with increased levels of the NFκB p65 subunit. Our results suggest that propofol induces an adaptive response by dual activation and crosstalk of cytoprotective PI3K/AKT and JAK2/STAT3 pathways. Rationale to apply propofol clinically as a preemptive cardioprotectant during cardiac surgery is supported by our findings.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics; The University of British Columbia; Vancouver, BC Canada.
authors.forename: Jayant
authors.initials: J
authors.lastname: Shravah
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics; The University of British Columbia; Vancouver, BC Canada.
authors.forename: Baohua
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics; The University of British Columbia; Vancouver, BC Canada.
authors.forename: Marijana
authors.initials: M
authors.lastname: Pavlovic
authors.affiliation: Faculty of Pharmaceutical Sciences; The University of British Columbia; Vancouver, BC Canada.
authors.forename: Ujendra
authors.initials: U
authors.lastname: Kumar
authors.affiliation: Department of Chemistry; The University of British Columbia; Vancouver, BC Canada.
authors.forename: David Dy
authors.initials: DD
authors.lastname: Chen
authors.affiliation: Centre for Heart Lung Innovation/Department of Pathology and Laboratory Medicine; The University of British Columbia; Vancouver, BC Canada.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics; The University of British Columbia; Vancouver, BC Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Ansley
keywords: JAK2/STAT3; PI3K/AKT; cardioprotection; crosstalk; propofol; signal transduction
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