Faculty and Staff Detail
|
Azza El-Remessy, Ph.D. Assistant Professor Director, Clinical and Experimental Therapeutics Program CET Clinical Administrative Pharmacy |
| Contact Information | |
|---|---|
| Phone: | (706) 721-6760 |
| Email: | aelremessy@mcg.edu |
| Fax: | (706) 721-3994 |
| Office: | HM-1219 |
| Address: |
UGA Clinical Pharmacy Program HM-1200 Medical College of Georgia Augusta, GA 30912 |
| Biosketch | |||
|---|---|---|---|
| B.Pharm | College of Pharmacy, Mansoura University | Mansoura, Egypt | 1991 |
| M.S. Biochemistry | College of Pharmacy, Mansoura University | Mansoura, Egypt | 1995 |
| Ph.D. | Ophthalmology Research, MCG and Mansoura College of Pharmacy, Mansoura University | Mansoura, Egypt | 1999 |
| Postdoctoral Fellow | Vascular Biology Center, Medical College of Georgia | Augusta, GA | 2000-2002 |
| Assistant Research Scientist | Vascular Biology Center, Medical College of Georgia | Augusta, GA | 2002-2005 |
| Instructor | Dept. of Pharmacology, Medical College of Georgia | Augusta, GA | 2005-2006 |
| Assistant Professor | College of Pharmacy, University of Georgia | Augusta, GA | 2006 to present |
| Adjunct Assistant Professor | School of Graduate Studies and Dept. of Pharmacology, School of Medicine, MCG | Augusta, GA | 2006 to present |
| Research Pharmacologist | VA Medical Center | Augusta, GA | 2006 to present |
- Honors and Awards
- 2005-2008 Scientist Development Grant from AHA/National.
2004 Young Investigator Travel Award from National Eye Institute.
2002-2004 Postdoctoral Fellowship from the American Heart Association.
2002 Young Scientist Travel Award from American Society for
Pharmacology and Experimental Therapeutics.
2000-2001 Post-doctoral Fellowship from ARVO/Ciba Vision Inc.
1996-1998 Pre-doctoral Fellowship from the Egyptian cultural & educational bureau.
1996 Honor Recognition for the MS from the Egyptian Syndicate of Pharmacy.
1991 Honor Student Recognition from the Egyptian Syndicate of Pharmacy.
- Area of Expertise
Diabetic retinopathy, a vascular-neurodegenerative disease is the leading cause of blindness in working age adults in US. Diabetic retinopathy is present to some degree in nearly all individuals who have had diabetes for more than 15 years, regardless of whether the diabetes is due to loss of insulin secretion (Type I) or to insulin resistance (Type II). So fare the treatment is limited to laser photocoagulation. This procedure is usually effective, but it destroys neural tissue and can decrease peripheral vision, impair night vision and change color perception. In order to identify new targets and develop new strategies to prevent diabetic retinopathy, it is crucial to understand the molecular mechanisms that regulate the function of retinal neurons and blood vessels.
Hyperglycemia is the primary pathogenic factor in the development of diabetes complications. We and others have shown also that diabetes and high glucose increase oxidative stress leading to reduced bioavailability of NO and increased formation of peroxynitrite. Peroxynitrite causes lipid peroxidation and nitration of tyrosine residues, inactivating key metabolic enzymes, and reducing cellular antioxidant defenses by oxidation of thiol pools. Previously, we have shown that diabetes-induced peroxynitrite formation as indicated by tyrosine nitration is correlated with retinal neuronal cell death, breakdown of brain retina barrier and inactivation of VEGF survival signal in diabetic retinas and isolated capillary cells. These studies suggest a key role of peroxynitrite in mediating different aspects of diabetes-induced vascular and neural pathology in the retina.
As part of my continued interest in the role of oxidative stress-induced vascular and neuronal injury, there are several ongoing projects:
1- Role of peroxynitrite-induced tyrosine nitration in inhibiting survival signaling pathway in endothelial cells. Our studies in microvascular endothelial cells demonstrate that high glucose or peroxynitrite increased cell susceptibility to apoptosis in the presence or absence of exogenous VEGF. Several studies showed the correlation between high glucose and increases in oxidative stress in various cell types. Our study was the first to elucidate the molecular mechanisms by which peroxynitrite alters VEGF survival pathway. In this study, I showed that tyrosine nitration of phosphatidyl inositol 3 (PI3)-kinase plays a crucial role in blocking VEGF/Akt pro-survival pathway and activating pro-apoptotic p38 MAP kinase pathway leading to accelerated cell death. Furthermore, blocking peroxynitrite formation or selective inhibiting of nitration blocks PI3-kinase nitration and restores PI3-kinase/Akt activity as well as cell survival.
2- Role of peroxynitrite in mediating VEGF-induced tyrosine phosphorylation via oxidation in endothelial cells.
Great part of effort is currently directed toward understanding of the physiological role of peroxynitrite in the angiogenic function of VEGF. Peroxynitrite is a powerful oxidizing and nitrating agent that causes oxidation of protein-associated thiol groups, lipid peroxidation, and nitration of tyrosine residues. So far, the focus of research on peroxynitrite in vascular disease has emphasized its potential role in inhibiting normal cell signaling pathways. We have reported significant increases in VEGF and peroxynitrite formation in diabetic rat retinas and in microvascular endothelial cells maintained in high glucose. However, recent studies indicate that peroxynitrite at low levels may also serve as a physiological regulator of metabolic pathways or as an intracellular messenger mediating the growth factor signal transduction. VEGF is a potent angiogenic growth factor that stimulates endothelial cell proliferation and migration in vitro and angiogenesis in vivo. Our studies in retinal endothelial cells showed that physiological level of peroxynitrite (1 mM) mimicks the effects of VEGF in activation of VEGFR2 and its down stream targets including Src kinase and focal adhesion kinase. Inhibiting peroxynitrite formation blocked VEGF action in stimulating endothelial cell proliferation, migration and alignment into tube-like structures. These results suggest the role of peroxynitrite in mediating VEGF’s angiogenic signal and function.
To elucidate the mechanism by which peroxynitrite mediates VEGF-stimulated neovascularization during pathological angiogenesis, a hypoxia-induced neovascularization mouse model is used to compare the effects of peroxynitrite decomposition catalyst, oxidation or nitration inhibitor on reducing neovascularization. Representative images of the results show that the pathological neovascularization (white circles) are blocked by the peroxynitrite decomposition catalyst (FeTTPs) or the oxidation inhibitor (N-Acetyl Cysteine, NAC) but not by the nitration inhibitor epicatechin. These results confirm the role of peroxynitrite via thiol oxidation rather than tyrosine nitration in mediating VEGF signal.
3- Role of peroxynitrite in diabetes-induced neuro-inflammation and degeneration.
Our lab has interest to study the role of tyrosine nitration and activation of p38 MAP kinase pathway in diabetes-induced neurotoxicity. Our data show that significant increases in tyrosine nitration and p38 MAP phosphorylation were associated with inflammatory mediators e.g. TNF-a, ICAM-1 and VEGF and neurotoxicity in diabetic retinas compared to normal controls. Our preliminary data show that selective blocking of tyrosine nitration restores neural cell survival function in diabetic animals. The studies of the role of peroxynitrite in altering nerve growth factor (NGF) signaling and alteration of its receptors: TrkA and P75NTR are currently investigated in diabetic animals. In parallel, the effects of high glucose and peroxynitrite on will be studied in isolated retinal ganglion cells to elucidate the molecular mechanisms by which peroxynitrite alters NGF’s function and signal and mediate neuronal cell death.
- Representative Publications
- Articles
A.B. EI-Remessv, A.M. EI-Gayar, A.M. Rabie, M. M.Elmazarand F. Ramadan. LCAT Activity, Apo A-I and HDL-cholesterol in Staging Patients with Hepato-splenic Bilharzasis. J. Mansoura Medical Bulletin. 15:234-241, 1994
A.B. EI-Remessv. A.M. Rabie, A.M. EI-Gayar, M.M. EI-Mazar and G. Shiha. Lipid and Lipoprotein Abnormalities in Hepatosplenic Bilharziasis. J. Benha Medical Bulletin. 19:567-577, 1995
Peer Reviewed publication
A.B. EI-Remessv, A.M. Rabie, M. M. EI-Shishtawy, L.A. Eissa, and G.I. Liou. Regulation of interphotoreceptor retinoid-binding protein gene expression by camp in differentiated retinoblastoma cells. Mol. Vision. Vol. 6:243-51, 2000
A.B. EI-Remessv, M.A. Behzadian, G. Abou-Mohamed, T. Franklin, R.W. Caldwell and R.B. Caldwell. Peroxynitrite causes increased vascular permeability in early experimental diabetes. Am. J. Pathology, 162 (6): 1995-2004, 2003
A.B. EI-Remessy, G. Abou-Mohamed, R.W. Caldwell and R.B. Caldwell. High glucose increases tyrosine nitration and superoxide anion formation in endothelial cells: role of eNOS uncoupling and aldose reductase activation. Invest. Ophthalmol. Vis. Sci., 44 (7) 3135-3143, 2003
A.B. EI-Remessv, I. Khalil, S. Matragoon, G. Abou-Mohamed, N. Tsai, R.W. Caldwell R.B. Caldwell and G. I. Liou. Neuroprotective effect of (-)D9-Tetrahydrocannabinol in NMDA-induced apoptosis in rat retina. Am. J. Pathology, 163(5): 1997-2008, 2003
X. Gu, A.B. EI-Remessy, S.E. Brooks, M. Al-Shabrawey, N. Tsai and R.B. Caldwell. Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite Am. J. Physiolgy, 285(3): C546-54, 2003
M. Al-Shabrawey, A.B. EI-Remessy, X. Gu, S. Brooks, M.S. Hamed, P.Huang and Ruth B. Caldwell. Normal Vascular development in mice deficient in endothelial NO synthase: Possible role of neuronal NO synthase. Mol. Vision 9: 549-558, 2003
G. Abou-Mohamed, J. Johnson, L. Jin, A.B. EI-Remessv, W. Kaesemeyer, R.B. Caldwell, R. W. Caldwell. Roles of superoxide, peroxynitrite and protein kinase C in the development of tolerance to nitroglycerin. J Pharmacol Exp Ther. 308:289-299, 2004.
A.B. EI-Remessy, M. Bartoli, D.H. Platt, D. Fulton and R.B. Caldwell. Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI-3 kinase nitration. J. Cell Science 118:243-52, 2005
M. Al-Shabrawey, M. Bartoli, A.B. El-Remessy, D.H. Platt, M.A. Behzadien, S. Matragoon, R.W. Caldwell and R.B. Caldwell. Inhibition of NADPH oxidase block retinal neovascularization in oxygen-induced retinopathy. Am. J. Pathology, 167:599-607, 2005
D.H. Platt, M. Bartoli, A.B. El-Remessy, T. Lemtalsi, D. Fulton and R.B. Caldwell. Peroxynitrite-mediated activation of VEGF Transcription in Vascular cells via signal transducer and activator of transcription-3. Free Rad. Biol. Med, 39: 1353-1361, 2005.
A.B. El-Remessy, M. Al-Shabrawey, Y. Khalifa, R.B. Caldwell and G.I. Liou. Neuroprotective and blood-retina barrier preserving effects of cannabidiol on experimental diabetes. Am. J. Pathology. 168: 235-244, 2006.
H. E. Tawfik, A.B. El-Remessy, S. Matragoon, R.B. Caldwell and R.W. Caldwell. Simvavstin improves diabetes-induced coronary endothelial dysfunction through superoxide reduction. J. Pharmacol. Exp. Therap. 319: 386-95, 2006
A.B. El-Remessy, Mohamed Al-Shabrawey, N. Ghaly, D.H. Platt, M. Bartoli, M.A. Behzadian, K. Motamed and R.B. Caldwell. Peroxynitrite mediates VEGF’s angiogenic signaling via nitration-independent mechanism. (submitted)
Reviews and book chapters
R. B. Caldwell, M. Bartoli, M. Ali Behzadian, A. B. El-Remessy, M. Al-Shabrawey, D.H. Platt and R.W. Caldwell. Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. J. Diabetes Metabolism Research and Reviews. 19: 442-455, 2003
R. B. Caldwell, M. Bartoli, M. Ali Behzadian, A. B. El-Remessy, M. Al-Shabrawey, D.H. Platt, G.I. Liou and R.W. Caldwell. Vascular endothelial growth factor and diabetic retinopathy: Role of oxidative stress. Curr. Drug Targets 4:411-4
- Other
- Grant support:
Molecular Mechanisms of VEGF’s angiogenic pathway: Role of Peroxynitrite
Agency: American Heart Association, National
Type: Scientist Development Grant
Principle Investigator: Azza El-Remessy
Period: January1, 2005 to December 31, 2008.
Total Award: $250,000
“Simvastatin protective effects of in Diabetic Retinopathy”
Agency: UGA Research Foundation
Type: Research Grant
Principle Investigator: Azza El-Remessy
Period: January 1, 2007 to December 31, 2007.
Total Award: $6,000
“Neuroprotective effects of statin in early Diabetic Retinopathy”
Agency: Pfizer Pharmaceutical
Type: Research Grant
Principle Investigator: Azza El-Remessy
Total Award: $55,000
Effort: 10 % (no salary)
03/01/2007-09/01/2008
Professional and learned societies:
1998- Association for Research in Vision and Ophthalmology (ARVO)
2002- American Society of Pharmacology & Experimental Therapeutics (ASPET)
2002- American Diabetes Association (ADA)
2003- AHA, Council on Basic Cardiovascular Sciences.
2005 American Society of Investigative Pathology (ASIP)
Scientific review responsibilities:
2005- Research Grants Council of Hong Kong
Reviewer for Academic Journals
J. Diabetes
J. Cellular Physiology
J. Experimental Cell Research
J. Clinical Investigation
J. Vascular Pharmacology
J. Current. Eye Res
J. Neuroscience
J. Acta Neuropathologica