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Propofol mediated cardioprotective signal transduction : ETAR dependence and caveolar effects in H9c2 cardiomyoblasts

University of British Columbia

Propofol is cardioprotective in the context of ischaemia-reperfusion. Components involved in propofol-mediated signaling involve AKT and STAT3. However, the involvement of the plasma membrane has not yet been elucidated. We hypothesized that propofol depends on two components located within the membrane — endothelin A receptor (ETAR) and caveolin. H9c2 cardiomyoblasts were propofol-treated. To determine propofol-signaling dependence on ETAR, the selective ETAR inhibitor, PD156707 was used, and pSTAT3 Y705 protein levels were measured as a functional outcome. Similarly, caveolar-dependence was determined by disrupting cellular lipid rafts with methyl-β-cyclodextrin. ETAR – AKT interaction was explored via Co-IP. Immunocytochemistry was used to determine if propofol was affecting the cellular localization of ETAR, Cav-1, AKT, or Cav-3. Cav-1 cellular localization was also investigated using discontinuous sucrose gradient fractionation. Propofol-mediated-signaling (via pSTAT3 Y705 levels) was significantly reduced upon the inhibition of ETAR. In contrast, lipid raft disruption failed to reduce propofol-mediated-signaling. Propofol did not affect localization/ interaction of AKT. ETAR protein levels increased in intracellularly with propofol. Cav-1 protein expression/ localization did not change. However, Cav-3 levels did increase in the nuclear region with propofol treatment. The results suggest that a component of propofol-signaling depends upon ETAR. Propofol signaling may act through a signalosome that involves receptor (ETAR) and Cav-3 internalization. This mechanism may be the avenue by which propofol is offering cardioprotection in a setting where other protection strategies are ineffective.

Text

2016-03-31

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/54930

Pharmacology and Therapeutics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/