Abstract
Many diseases and pathological conditions including ischemia/reperfusion (I/R) injury are the consequence of the actions of reactive oxygen species (ROS). Controlling ROS generation or its level may thus hold promise as a standard therapeutic modality for ROS related diseases. Here, we assessed heme oxygenase-1 (HO-1), which is a crucial antioxidative antiapoptotic molecule against intracellular stresses, for its therapeutic potential via its inducer hemin. To improve the solubility and in vivo pharmacokinetics of hemin for clinical applications, we developed a micellar hemin by conjugating it with poly(ethyleneglycol) (PEG): PEG-hemin. PEG-hemin showed higher solubility in water and significantly prolonged plasma half-life than free hemin, which resulted from its micellar nature with molecular mass of 140 kDa in aqueous media. In a rat ischemia/reprefusion (I/R) model, administration of PEG-hemin significantly elevated HO-1 expression and enzymatic activity. This induction of HO-1 led to significantly improved liver function, reduced apoptosis and thiobarbituric acid reactive substances (TBARS) of the liver, and decreased inflammatory cytokine production. PEG-hemin administration also markedly improved hepatic blood flow. These results suggest that PEG-hemin exerted a significant cytoprotective effect against I/R injury in rat liver by inducing HO-1 and thus appears potential therapeutic for ROS-related diseases including I/R injury.
- Received June 23, 2011.
- Revision received September 2, 2011.
- Accepted September 2, 2011.
- The American Society for Pharmacology and Experimental Therapeutics