Abstract
Heme oxygenase-1 (HO-1) is emerging as an important cytoprotective enzyme system in a variety of injury models. To optimize future therapeutic applications of HO-1, it is necessary to delineate the precise functions and mechanisms as well as modes of externally regulating HO-1 expression. Investigations have been limited by difficulties with the generation of HO-1 null mice and the lack of specific HO-1 inhibitors. Lung ischemia-reperfusion (I-R) injury is the inciting event in acute lung failure following transplantation, surgery, and shock. To study the function of HO-1 in I-R-induced lung injury, we designed small interfering RNA (siRNA) sequences that effectively suppress HO-1 expression both in vitro and in vivo in an organ-specific manner. In this study we show that there is enhanced apoptosis, via increased Fas expression and caspase 3 activity, in the presence of HO-1 siRNA in endothelial cells and mouse lung during I-R injury, whereas HO-1 overexpression attenuates apoptosis. To the best of our knowledge, we are the first to demonstrate that lung-specific siRNA delivery can be achieved by intranasal administration without the need for viral vectors or transfection agents in vivo, thereby obviating potential concerns for toxicity if siRNA technology is to have clinical application in the future.
Highlights
HO-11 is one of three isoforms of HO, the rate-limiting enzyme in the degradation of heme to biliverdin and eventually to bilirubin
We demonstrate that intranasal small interfering RNA (siRNA) delivery, without a vector or transfection agent, has lung specificity and that Heme oxygenase-1 (HO-1) potently regulates lung apoptosis
HO-1 siRNA Inhibits A-R-induced HO-1 Protein Expression in pulmonary artery endothelial cells (PAEC)—We have shown previously [14] that mouse lungs subjected to I-R injury or endothelial cells exposed to A-R induce HO-1 expression
Summary
HO-11 is one of three isoforms of HO, the rate-limiting enzyme in the degradation of heme to biliverdin and eventually to bilirubin. To study the function of HO-1 in I-R-induced lung injury, we designed small interfering RNA (siRNA) sequences that effectively suppress HO-1 expression both in vitro and in vivo in an organ-specific manner.
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