Cytoprotection by HMOX1

HMOX1 confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and immune cell proliferation. It binds to the NACHT domain of NLRP3 inflammasome, blocking its activation. In mouse it directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation. It also blocks phosphorylation of STAT3 by PTK6 and co-inhibits Socs3, a negative feedback factor of Stat3 activation, as well as RORγt, thereby decreasing Th2 and Th17 immune responses, and alleviating airway inflammation.

The beneficial effects of the three products generated by HMOX1 differ not only in their inherent molecular mechanisms, but also in their downstream cellular targets. To date, this is the only enzymatic system known to exhibit such characteristics. Iron is a vital component of many biological systems and is capable of producing hydroxyl radicals via fenton chemistry. For this reason, iron is sequestered by the storage multimer ferritin and to prevent oxidative damage while maintaining the iron pool. On the other hand, the protective effects of bilirubin and CO are broadly recognized, which has led to their consideration as therapeutics for a range of diseases. Bilirubin has been recognized as one of the most potent antioxidants in nature, and moderate increases of its serum level have been shown in numerous large-scale population and epidemiological studies to have a protective effect against cardiovascular and metabolic disease. These effects are mediated by bilirubin scavenging of superoxide anions and reactive nitrogen species (RNS), and by activating the transcription factor PPAR-alpha.

CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. CO possesses intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. Binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics. The most important of these is the mitochondrial cytochrome c oxidase (Cco). By locally blocking mitochondrial respiration the main source of reactive oxygen species (ROS) in the cell is switched off. Additionally CO enables efficient reduction of methemoglobin (MetHb) by H2O2, thus preventing the generation of free heme in hemorrhagic diseases and malaria.