Altered states of oxygen tension (pO 2) above and below physiological levels can also modulate ROS production from mitochondrial metabolism. HO-1 responds to pro-oxidant states associated with enhanced reactive oxygen species (ROS) generation, as can be produced from dysfunctional mitochondria (mtROS) or activated inflammatory cells. Further, a broad class of electrophilic plant-derived polyphenolic compounds including flavonoids and other natural antioxidants are potent inducers of HO-1. HO-1 expression responds to many diverse chemical and physical agents, including the substrate heme, a pro-oxidant compound, oxidants (e.g., H 2O 2), exposure to ultraviolet-A radiation, nitric oxide (NO), heavy metals and other thiol-reactive chemicals. Furthermore, additional pioneering studies established HO-1 as an antagonist of TNF-induced endothelial cell apoptosis. Accumulating research since then has revealed that HO-1 can exert pleiotropic roles in mitigating inflammation, via multiple molecular mechanisms including modulation of p38 mitogen-activated protein kinase (MAPK) activity. Seminal studies on the macrophage inflammatory response established HO-1 as an anti-inflammatory mediator, which can limit Toll-like receptor-4 (TLR4)-dependent pro-inflammatory cytokine(s) production in activated macrophages. The essential role of HO-1 in human physiology was also underscored by a unique case of HO-1 genetic deficiency in a human subject, who bore symptoms of systemic endothelial cell injury, anemia, and abnormal tissue iron accumulation. Furthermore, these mice and endothelial cells derived from these mice were highly susceptible to oxidative stress. These mice were characterized by abnormal systemic iron metabolism including hepatic and renal iron deposition and anemia. The importance of HO-1 in systemic homeostasis and iron balance was deduced from early studies using mice genetically deficient in HO-1 ( Hmox1 −/−). Investigations in the mid-1980s established HO-1 as identical to a 32 kDa shock protein regulated by multiple forms of chemical and physical cellular stress, including oxidizing ultraviolet-A radiation, and heavy metals. The HO-1 field continues to attract worldwide research interest, from its mechanistic roles in regulating fundamental biological and metabolic processes, to its continuing status as a candidate therapeutic target in many disease states. This review will summarize the roles of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease. While autophagy is primarily associated with cell survival, its occurrence can coincide with RCD programs. HO-1 has also been implicated in co-regulation of autophagy, a cellular homeostatic program for catabolic recycling of proteins and organelles. In contrast, in ferroptosis, HO-1 may play a pro-death role via enhancing iron release. HO-1 may provide anti-inflammatory protection in necroptosis or pyroptosis. While the antiapoptotic potential of HO-1 and its reaction product CO in apoptosis regulation has been extensively characterized, relatively fewer studies have explored the regulatory role of HO-1 in other forms of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). A large body of work has also implicated HO-1 as a cytoprotective molecule against various forms of cell death, including necrosis, apoptosis and newly recognized regulated cell death (RCD) programs such as necroptosis, pyroptosis, and ferroptosis. HO-1 has been implicated as a key mediator of inflammatory cell and tissue injury, as validated in preclinical models of acute lung injury and sepsis. The substrate, heme, is a potent pro-oxidant that can accelerate inflammatory injury and promote cell death. The inducible form of the enzyme, heme oxygenase-1 (HO-1), exerts a central role in cellular protection. Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron.
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |