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FISCUS, Ronald R.


B.Sc. (1968) Iowa State University
M.Sc. (1975) Iowa State University
Ph.D. (1979) Iowa State University

Research Interests:
Cardiovascular and Neural Physiology.
Interactions between bioactive peptides, nitric oxide (NO), and oxygen free radicals and
involvement in the pathogenesis of septic shock and ageing-related diseases of blood vessels and nerves.

Research Interests: Cardiovascular and Neural Physiology.
Interactions between bioactive peptides, nitric oxide (NO), and oxygen free radicals and involvement in the pathogenesis of septic shock and ageing-related diseases of blood vessels and nerves.

Our laboratory is currently studying signal transduction mechanisms (cellular mechanisms) and pathological role of nitric oxide (NO) and certain bioactive peptides (e.g. atrial natriuretic factor [ANF], brain natriuretic peptide [BNP], and calcitonin gene-related peptide [CGRP]) in the cardiovascular and nervous systems. Of specially interest is mechanisms and involvement of NO and CGRP as mediators of the life-threatening drop in arterial blood pressure during severe sepsis (i.e. septic shock) and as anti-proliferative agents inhibiting the growth of vascular smooth muscle cells, helping to protect arteries against development of ageing-related diseases, such as atherosclerosis, coronary heart disease, and stroke. For example, our laboratory has shown that CGRP and NO act synergistically to cause vasorelaxation and inhibition of smooth muscle cell proliferation via signal transduction mechanisms involving interactions between cyclic AMP and cyclic GMP pathways. We have identified CGRP as a important contributor to the vascular impairment and drop in blood pressure during endotoxicosis in animal models and during sepsis (both gram-negative and gram-positive bacteraemia) in human patients. We have also shown that inflammatory agents (bradykinin, histamine, and prostaglandins) and a metabolic end-product (lactic acid) trigger release of CGRP from nerves. Because levels of lactic acid, bradykinin, histamine and prostaglandins are all elevated during septic shock, these agents likely play a key role in stimulating CGRP release during shock, ultimately causing the devastating drop in blood pressure. Our data further suggests that CGRP plays an important role as vasodilator in other conditions with elevated levels of lactic acid, such as strenuous exercise and myocardial & brain ischaemia.

Our laboratory is also currently studying the involvement of cyclic GMP and cyclic GMP-dependent protein kinase (PKG) in the protection against cell death (apoptosis and/or necrosis). Collaborative research between our laboratory and a laboratory in the United States has shown that a newly-discovered neurotrophic factor, the secreted form of ß-amyloid precursor protein (ß-APPS), can increase the survival of hippocampal neurons during stressful conditions, such as exposure to toxic levels of glutamate. Using radioimmunoassay techniques and specific inhibitors of PKG, we have identified the cyclic GMP/PKG signal transduction pathway as the most likely intracellular mediator of this neuroprotective response of ß-APPS.

Our laboratory at the Chinese University of Hong Kong has found that the cardiac hormone BNP, which also activates the cyclic GMP/PKG pathway in neurons, delays the onset of apoptotic cell death caused by deficiency of neurotrophic factors. We determine apoptosis by measuring DNA fragmentation, identified by DNA laddering on agarose gel electrophoresis, and by morphological changes at both the light microscopy and electron microscopy (EM) levels. Currently, we are determining the involvement of gene expression of "neuroprotective" genes activated by the cyclic GMP/PKG pathway, using Northern blot and Western blot analyses as well as immunohistochemical localization of the expressed proteins. We believe that the neuroprotective effect of ß-APPS in hippocampal neurons is an important protective mechanism, slowing down the ageing process in neurons and thereby delaying the onset of neuronal cell death that would lead to Alzheimer's disease (senile dementia of the Alzheimer's type). Furthermore, we believe that the neuroprotective effect of the cardiac hormone BNP is an important physiological mechanism that prevents apoptosis of neurons within the heart during periods of stress, such as myocardial infarction (MI).

In vivo models (live animal models) and in vitro models (cell cultures of neural and vascular cells, brain & spinal cord slices, and isolated, perfused heart & vascular rings) are used in our laboratory to study: 1) mechanisms of release of CGRP and NO, 2) signal transduction mechanisms of CGRP- and NO-induced vasorelaxation and inhibition of vascular smooth muscle cell growth, and 3) expression of cytoprotective genes and protection against onset of apoptosis/necrosis caused by removal of essential neurotrophic factors or exposure to cytotoxic agents (e.g. oxygen free radicals and peroxynitrite). Cytoprotection is determined by cell survival assays, inhibition of DNA laddering (assessed by both agarose gel electrophoresis and the newly-developed technique of capillary electrophoresis [CE] with laser-induced fluorescence [LIF] detection), inhibition of lactate dehydrogenase (LDH) release, and prevention of nuclear condensation and membrane disruption assessed by EM.

Our laboratory currently has an active research collaboration with the Institute of Vascular Medicine, Beijing Medical University, Beijing, China, to study cellular mechanisms of vascular restenosis occurring after laser angioplasty. This collaborative project is funded by grants from the United States. Other projects in our laboratory, described above, are well funded by an Earmarked Grant and other grants from Research Grants Council of Hong Kong.

Selected Publications:

* Fiscus, R. R., Hao, H.,Wang, X., Arden, W.A. & Diana, J.N. (1994) Nitroglycerin (exogenous nitric oxide) substitutes for endothelium-derived nitric oxide in potentiating vasorelaxations and cyclic AMP elevations induced by calcitonin gene-related peptide (CGRP) in rat aorta. Neuropeptides 26: 133-144.

* Barger, S.W., Fiscus, R.R., Ruth, P., Hofmann, F. & Mattson, M.P. (1995) Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of beta-amyloid precursor. J. Neurochem. 64: 2087-2096

* Wang, X., Fiscus, R.R., Yang, L. & Mathews, H.L. (1995) Suppression of the functional activity of IL-2-activated lymphocytes by CGRP. Cell. Immunol. 162: 105-113.

* Wang, X., Wu, Z., Tang, Y., Fiscus, R.R. & Han, C. (1996) Rapid nitric oxide- and prostaglandin-dependent release of calcitonin gene-related peptide (CGRP) triggered by endotoxin in rat mesenteric arterial bed. Br. J. Pharmacol. 118: 2164-2170.

* Tang, Y., Han, C., Fiscus, R.R. & Wang, X. (1997) Increase of calcitonin gene-related peptide (CGRP) release and mRNA levels in endotoxic rats. Shock 7: 225-229

* Wang, X. & Fiscus, R.R. (1997) Lactic acid potentiates bradykinin- and low pH-induced release of CGRP from rat spinal cord slices. Am. J. Physiol. 273: E92-E98.

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