Hemoproteins carry out many diverse biological functions integral to life, ranging from oxygen storage to electron transfer for energy production and enzymatic biotransformation of steroids and xenobiotics. The cellular level of heme is regulated in part by the heme oxygenase (HO) system. Perturbations by toxic metals and environmental agents in heme metabolism cause significant changes in steroidogenesis in the adrenals. Adrenal steroids, in turn, have profound effects on the brain. We have characterized two forms of HO enzyme: HO-1, which was identified as a metal-inducible protein nearly 2 decades ago, is now recognized as a stress or heat shock protein (HSP32) and is inducible by oxidative stress, toxic heavy metals and environmental agents. Induction of HSP's is an important and universal protective cellular response to environmental insults. HSP's have a unique role in cell biology, from chronic neurodegenerative diseases to immunity and cancer. HO-2, which is the predominant form in the brain, is not a stress protein. Recently, the products of heme degradation, bile pigments and CO, are shown to have major physiological functions. Bile pigments display antiviral activity against HIV and herpes virus and are potent antioxidants; oxygen radicals are suspected in etiology of neurodegeneration. While CO is suspected to function similar to nitric oxide (NO) as a neurotransmitter to stimulate cGMP production in the brain. In this organ HO-2 is the main source for Co production. In addition, enzymes that generate cCMP and NO are hemoproteins, and likely substrates of HO enzymes. In systemic organs NO influences tumor growth, and vascular tone. The sustained levels of NO are suspected to be the cause of neuronal death in Parkinson's disease and Alzheimer's dementia. Collectively, these developments suggest the vital function of HO system in health and disease and dictate the need for further understanding the regulation and function of the isozymes. This is the overall objective of the present proposal, and the Specific Aims are: l) To develop transgenic (Tg) mouse models for examination in vivo and in vitro role of HO isozymes in oxygen radical and metal-mediated damage to the brain; neuronal specific and human beta-actin promotor constructs will be used to overexpress HO-1 or HO-2. 2) To examine whether induction of HO-1 protects renal functions against ischemia/reperfusion injury and nephrotoxicants. 3) To examine the effects of aging and changes in profile of adrenal glucocorticoids caused by heavy metals on regulation and function of HO isozymes and heme-dependent activities in brain. 4) To investigate the role of HO isozymes in regulation in vivo and in vitro synthesis of NO and production of cGMP.
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