Oxygen sensing and Lead (Pb) toxicities: Molecular interactions, cell signaling &antioxidant defense

Hypoxia is one of the most serious factors that can directly impair the function of metabolic pathways in the cell. Cellular hypoxia causes an initiation of hypoxia-response genes responsible for angiogenesis, oxygen transport, and metabolism. Hypoxia leads to alter intracellular chemical microenvironment by increasing calcium concentration ([Ca۲+]i), ۵-lipoxygenase, lipid peroxidation, cycloxygenase (COX), constitutive nitric oxide synthase (cNOS), leukotriene B۴ (LTB۴), prostaglandin E۲ (PGE۲), interlukins, tumor necrosis factor-α (TNF- α), caspases, complement activation heat shock protein ۷۰ kDa (HSP-۷۰), and hypoxia-inducible factor- ۱α (HIF-۱α). Another key molecule within this hypoxia-induced response is the presence of nitric oxide (NO). It is synthesized by nitric oxide synthases (NOS) and its release can be stimulated as a result of inflammatoryresponses, sympathetic activation and drop in oxygen levels. Interestingly hypoxia and divalent heavy metal like lead (Pb) generates ROS and disturbed oxidant/antioxidant balance which is linked to the transcriptional factor hif- ۱α. The results from the author’s study showed both divalent cationic heavy metal (Pb) or chronic sustained hypoxia stimulates the production of hif-۱α transcription factor and VEGF gene expression in metabolically active tissues in similar molecular mechanism.