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.

The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats

“…. It was shown that propofol protection can be achieved by activation and crosstalk between PI3P/AKT and JAK2/STAT pathways, as well as by activated MAPK/ERK cascade, through a very fast phosphorylation of signaling pathways (10-60 min) and translocation of transcription factors (up to 4 h) after propofol exposure (Shravah et al 2014;Kidambi et al 2010). Our studies in vivo showed also that propofol led to early activation of pro-survival Akt and ERK1/2 kinases, changed expression c-fos, and NfKb transcription factors, and might have suppressed the last step of apoptotic cascade inhibiting caspase-3 activity by XIAP overexpression (Milanovic et al 2014;Popic et al 2015).…”

Propofol Cardioprotection against Myocardial Ischemia- Reperfusion Injury: A Mechanistic Review

“…Propofol improved cardiac function and ameliorated hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis via activating HO-1/STAT3 pathway [82]. It was also suggested that propofol not only induced JAK2/STAT3, but also PI3K/Akt activation in cultured H9c2 cells in a concentration-dependent manner [83].…”

“…It was reported that activation of NFB could transcriptionally induce Bcl-2 expression in pancreatic cells [85]. Propofol could induce the perinuclear translocation of NFB p65 subunit and enhance cell survival in cardiac H9c2 cells [83]. On the other hand, propofol could also reduce LPS-induced inflammatory responses in macrophages by inhibiting ROS-induced NFB activation [86].…”

Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial

“…40 Unlike inhalational anesthesia, the mechanism may involve transcription factor STAT3, which doesn't require a second messenger system for signal transduction. 41 Release of ROS would subsequently be attenuated, and 15-F 2t -isoprostane generation would decline. This protective response, termed mitochondrial hormesis (i.e., mitohormesis), could prevent injury and remodelling of the ischemic-reperfused heart.…”