Hamdy Hassanain, PhD

Current OSU Appointments

Assistant Professor, Anesthesiology

Adjunct Assistant Professor, Internal Medicine

Abstracts

Hassanain H., Kopachick W. 1989. "Inactivation of growth gene expression in Dictyostelium." Abstract. Journal of Cellular Biochemistry; Supplement 13B, pp. 12 (UCLA Symposia on Molecular & Cellular Biology,1/21 to 2/11/89)..

Hassanain H, Gupta S. 1993. "Induction of Indoleamine 2,3-Dioxygenase Gene expression by Interferon-γ: Identification of An Interferon-γ Induced DNA-binding Factor (B349)." Abstract. J. Cell. Biochem.;Supplement 17A, 1993, January 9-31,1993 (Keystone Symposia on Molecular and Cellular Biology)..

Hassanain H, Chon S, Gupta S. 1994. "Enhanced binding of transcription factors to DNA in the presence of detergents (I324)." Abstract. J. Cell. Biochem.; Supplement 18B, 1994, January 21-February 13, 1994 (Keystone Symposia on Molecular and cellular Biology)..

Hassanain H, Ray S, Chiu IM. 1998. "Isolation of a human Zic2 homolog, a putative regulator of FGF-1 in gliomas." Abstract. J. Cell. Biochem. (March 1-7), (Keystone Symposia in Signal transduction)..

Hassanain H, Sarker KD, Parker-Thornburg J, Flavahan S, Wang T, Kolattukudy P, Strauch AR, Morris, M., and Pascal J. Goldschmidt-Clermont. 1999. "Transgenic mice over-expressing Rac within smooth muscle." Abstract. Circulation (Supplement) (#3200, page I-607). The 72nd Scientific Sessions, Atlanta, Georgia, Nov. 7-10, 1999..

Hassanain H., Lopes N, Marialuisa M, Selvakumar B, Sarker DK, Strauch RA, Nuovo JG, Morris M, Zweier J, Goldschmidt-Clermont PJ. 2000. "Transgenic smooth muscle cell expression of an activated Rac mutant induces hypertension." Abstract. Abstract accepted for AHA 73rd Scientific Sessions, New Orleans. Nov.12-15, 2000..

Al-kheraije K, Wunderlich JE, Strauch AR, Morris M, Hassanain HH. 2001. "The Role of Profilin in vascular smooth muscle contractility and hypertension in a transgenic mouse model." Abstract. Circulation, the 74th Scientific Sessions, 2001, Anaheim, California..

Hassanain H, Irshaid I, Al-kheraije K, Michler RE, Goldschmidt-Clermont PJ. 2001. "Smooth muscle cell expression of a constitutive active form of human Rac 1 accelerates wound repair." Abstract. Keystone Symposia in Angiogenesis and Chronic Diseases and Cellular and Molecular Events in the Pathogenesis of Atherosclerosis (April 24-29).. [Editor Reviewed]

Wunderlich JE, Al-kheraije K,.Michler RE, Goldschmidt-Clermont, Hassanain HH. 2001. "Expression of a constitutively activated mutant of human Rac1 gene accelerate wound repair." Abstract. ISMICS Fourth annual Scientific Meeting. Munich, Germany-June 27-30.

Al-kheraije K, Wisel S, Hassanain H. 2002. "Changes in actin dynamics lead to activation of the hypertrophic signaling cascade in the vascular smooth muscle cells of a transgenic mouse model." Abstract. Abstract accepted for AHA 75rd Scientific Sessions, Chicago. Nov.17-20, 2002..

Al-kheraije K, Wisel S, Rigatto KV, Irshaid F, Mitchell SA. Morris M, Hassanain H. 2002. "Expression of Profilin in vascular smooth muscle cells leads to vascular hypertrophy and hypertension in a transgenic mouse model." Abstract. Abstract accepted for AHA 75rd Scientific Sessions, Chicago. Nov.17-20, 2002..

Deepali AP, Hassanain H, Goldschmidt P, Bauer. 2002. "Oxidative stress as an important participant in urinary bladder dysfunction and remodeling: the use of transgenic model." Abstract. Graduate & Postgraduate Research Day at OSU Medical Center, 4/3/02..

J Guzman, J Palmer, JG Yu, Z Suntres, J Xue, HJ Cooke, S Wisel, R Michler, HH Hassanain, FL Christofi. 2003. "Amplification and immune modulation in the AC/cAMP signaling pathway leads to hyperexcitability in intrinsic primary afferent (AH) neurons in Trichinella spiralis infected guinea pigs." Abstract. Distinguished Plenary Session Abstract. Digestive Disease Week, Orlando, Florida, May 2003.

Rigatto KV, Morrris M, Hassanain H. 2003. "Baroreflex sensitivity is decreased in a transgenic mouse model which overexpresses the Rac protein." Abstract. Abstract accepted for AHA 76rd Scientific Sessions, Florida. Nov. 17-20, 2003..

Wisel S, Coats P, Hassanain H. 2003. "Dysregulation of Rac 1 and vascular remodeling." Abstract. Abstract accepted for AHA 76rd Scientific Sessions, Florida. Nov.17-20, 2003..

Moustafa BM, Coats P, Wisel S, Wolf B, Hassanain H. 2004. "Dysregulation of Rac1 leads to changes in blood pressure and vascular remodeling in transgenic mouse models." Abstract. Abstract accepted for Oral Presentation at Sport Medicine Scientific Meeting, Indiana. June 1-3, 2004..

Wolf BJ, Wisel S, Mortensen R, Christofi F, Awad L, Hassanain H. 2004. "Generation of two C-reactive protein transgenic mouse lines." Abstract. 3rd Annual OSUMC Graduate & Postgraduate Research Day, Columbus Ohio. April 1, 2004..

Chen Z, Guzman JE, Palmer J, Yu JG, Cooke HJ, Xue J, Javed A, Grants I, Hassanain HH, Suntres Z, Christofi F. 2005. "Amplification in the AC/cAMP signaling pathway is linked to neuroplasticity in myenteric AH neurons during acute infection with Trichinella spiralis in guinea pigs." Abstract. 4th Congress of the International Society for Autonomic Neuroscience, July 12-17, 2005, Marseille, France..

Moustafa-Bayoumi M, Hassanain HH, Kirby TE, Devor ST, Kukielka M, Billman GE. 2006. "Cardiac Responses to Endurance Training in a Canine Model of Sudden Death." Abstract. Experimental Biology meeting, April 1-5, 2006.

Moustafa-Bayoumi M, Hassanain HH, Kirby TE, Devor ST, Kukielka M, Billman GE. 2006. "Cardiac Responses to Endurance Training in a Canine Model of Sudden Death." Abstract. Experimental Biology meeting, April 1-5, 2006.

Moustafa-Bayoumi M, Kirby TE, Devor ST, Hassanain HH. 2006. "Endurance Training Induces Physiological Cardiac hypertrophy Post Myocardial Infarction without Affecting Calcineurin Signaling." Abstract. AHA, November 12-15, 2006.

Moustafa-Bayoumi M, Reiser PJ, Hassanain HH, Devor ST, Kirby TE, Kukielka M, Billman GE. 2006. "Endurance training decreased Myosin Heavy Chain Type I in Canine Skeletal Muscle Without Changing Calcineurin A Protein Expression." Abstract. The 53rd ACSM annual meeting, May 31-June 3, 2006.

Scipio P, Sun G, Alhaj M, Christofi FL, Awad H, Hassanain HH. 2007. "The Role of C-Reactive Protein (CRP) in Atherosclerosis Causal Link or Simple Association?." Abstract. The Ohio State University Research Day, March 28, 2007.

Hassona MDH, Abouelnaga ZA, Alhaj MA, Moustafa-Bayoumi M, Hassanain HH. 2008. "Biomechanical stress in VSM cells leads to vascular remodeling and hypertension in profilin 1 transgenic mouse model." Abstract. Experimental Biology meeting, San Diego, California, April 4-10, 2008..

Hassona MDH, Abouelnaga ZA, Alhaj MA, Moustafa-Bayoumi M, Hassanain HH. 2008. "Cardiac overexpression of active Zea maize RacD in transgenic mice deteriorates postischemic contractile recovery." Abstract. Experimental Biology meeting, San Diego, California, April 4-10, 2008..

Abouelnaga ZA, Hassona MDH, Awad M, Alhaj MA, Badary OA, Hamada F, Bergese SD, Hassanain HH. 2009. "Mechanical strain in VSMC triggers vascular remodeling and hypertension and activates integrins in Profilin1 transgenic model." Abstract. Experimental Biology.

Awad M, Talukder H, Kulkarni A, Abouelnaga ZA, Hassona MDH, Alhaj M, Zweier J, Kuppusamy P, Bergese SD, Hassanain HH. 2009. "Hypertrophy and postischemic contractile dysfunction in mice overexpressing the active form of Zea maise RacD in the heart." Abstract. Experimental Biology.

Hassona MDH, Abouelnaga ZA, Awad M, Alhaj MA, Wani A, Bergese SD, Hassanain HH. 2009. "Vascular hypertrophy-associated hypertension of Profilin1 transgenic mouse model led to functional remodeling of vasculature." Abstract. Experimental Biology.

Chapters In Books

Hassanain H, Goldschmidt-Clermont PJ. 1999. Rac, superoxide, and signal transduction. In Antioxidant and Redox Regulation of Genes. Edited by C. Sen. x: Academic Press.

Degrees

1974	B.S., Alexandria University, Genetics

1984	M.S., University of Illinois, Microbiology

1990	Ph.D., Michigan State University, Molecular and Development Biology

Fellowship, Internship or Residency

1975 - 1978

Research Assistantship, Genetics, Ministry of Health, Alexandria, Egypt.

01/75 - 12/78

Research Fellow, Cytogenetic analysis of patients with genetic disorders, Ministry of Health and Population of Egypt, Cairo, Egypt.

1979 - 1982

Instructor, Teaching Principles of Genetics, Alexandria University, Alexandria, Egypt.

1982 - 1984

Graduate Research Assistant, Department of Microbiology, Project: Assessment The Phosphoribosyl Anthranilate Isomerase (PAI) Activity in Yeast Strains Containing Multi-Copy of PAI Gene, University of Illinois, Urbana-Champaign, IL, United States.

1984 - 1985

Graduate Teaching Assistantship, Department of Zoology, Teaching: The Principles of Developmental Biology, Michigan State University, East Lansing, MI, United States.

1985 - 1986

Graduate Research Fellowship, Department of Cellular and Molecular Biology, Training Program for Ph. D. Students, Project: Assess the regulation of phenoxazinone synthase gene in Streptomyces antiboticus, University of Michigan, Ann Arbor, MI, United States.

1986 - 1989

Graduate Research Assistant, Department of Zoology, Study the regulation of growth specific-genes in Dictyostelium discoideum, Michigan State University, East Lansing, MI, United States.

Honors

1992 - 1994

Fellow, The Blackie Floyd Fraternal Order of Eagles Cancer Research Fellowship. Fraternal Order of Eagles. Hipple Cancer Research Center, Dayton, OH, United States. Subject: Cancer Research

2008	February 21, 2008 OSU Research News. The Ohio State University, Columbus, OH, United States.

Inventions and Patents

Hassanain HH, Primary inventor, Patent filing 2000 (patent pending). Develop Transgenic Mouse Models That Express either the Constitutively Active or Dominant Negative Mutants of Human Rac Gene in Blood Vessels as Models for Hypertension and Wound Healing. . 50% Authorship: I developed the models.

Hassanain HH, Co-inventor, Patent filing 2000 (patent pending). Rac-Like Genes and Methods of Use. . An internaltional patent was filed with the Pioneer Hi-Bred International Inc. 33% Authorship: I cloned eight corn Rac isoforms in mammalian expression vectors and tested them in mammalian tissue culture (Hassanain et al, BBRC 2000).

Hassanain HH, Co-inventor, Patent filing 2000 (patent pending). Rac-Like Genes and Methods of Use of Platelet Polymorphism PL-A2 to Diagnose Risk of Thrombotic Diseases. . Pioneer Hi-Bred International Inc. 33% Authorship: I am co-inventor ; I cloned eight corn Rac isoforms in mammalian expression vectors and tested them in mammalian tissue culture.

Hassanain HH, Primary inventor, Patent filing 2001 (patent pending). Transgenic Mouse Models That Express Plant Rac D Gene in Heart as a Model for Cardiomyopathy. . 50% Authorship: I developed the models.

Hassanain HH, Co-inventor, Patent filing 2008 (patent pending). Activated overexpressed Rac1 can induce Kaposi' Sarcoma (KS): Rac1 inhibitors of ROS induced by Rac1 can inhibit KS cells. . 17% Authorship: I developed the transgenic mouse model.

Memberships

1995 - present

Member. American Cancer Society

1997 - present

Member. American Heart Association

2002 - present

Member. American Heart Association. American Heart Association - Hypertension Section

2007 - present

Member. American Society of Biochemistry and Molecular Biology

Peer Reviewed Journal Articles

Hassanain, H., and Kopachick, W. 1989. Regulatory signals affecting a selective loss of mRNA in Dictyostelium discoideum. Journal of Cell Science. Vol. 94 ( Pt 3): 501-509.

Hassanain, H., Chon SY, and Gupta, S. 1993. Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-gamma and -alpha. Analysis of the regulatory region of the gene and identification of an interferon-gamma-inducible DNA-binding factor. Journal of Biological Chemistry. Vol. 268, no. 7: 5077-5084.

Hassanain, H; Dai, W; Gupta, S L. 1993. Enhanced gel mobility shift assay for DNA-binding factors. Analytical Biochemistry. Vol. 213, no. 1: 162-7.

Dai W., Pan H., Hassanain, H., Gupta, S. and Murphy, MJ Jr. 1994. Molecular cloning of a novel receptor tyrosine kinase, tif, highly expressed in human ovary and testis. Oncogene. Vol. 9, no. 3: 975-979.

Chon, S., Hassanain, H., Pine, R., and Gupta, S. 1995. Involvement of two regulatory elements in interferon-gamma-regulated expression of human indoleamine 2,3-dioxygenase gene. J Interferon Cytokine Res. Vol. 15, no. 6: 517-526.

Chon, S., Hassanain, H., and Gupta, S. 1996. Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene. Journal of Biological Chemistry. Vol. 271, no. 29: 17247-17252.

Hassanain, H., Yogesh, K.S., Moldvan, L., Khrasmtsov, V., Berliner, L.J., Duvick, J.P., and Goldschmidt-Clermont, P.J. oldschmidt-Clermont, P J. 2000. Plant rac proteins induce superoxide production in mammalian cells. Biochemical and Biophysical Research Communications. Vol. 272, no. 3: 783-788.

Ying AK, Hassanain, H., Roos, C.M., Smiraglia, D.J., Issa, J.J., Michler, R.E, Caligiuri, M., Plass, C., Goldschmidt-Clermont, P.J. 2000. Methylation of the estrogen receptor-alpha gene promoter is selectively increased in proliferating human aortic smooth muscle cells. Cardiovascular Research. Vol. 46, no. 1: 172-179.

Nowicki, P,T., Flavahan, S., Hassanain, H., Mitra, S., Holland, S., Goldschmidt-Clermont, P.J., and Flavahan, N.A. 2001. Redox signaling of the arteriolar myogenic response. Circulation Research. Vol. 89, no. 2: 114-116.

Lopes N, Gregg DG, Vasudevan S, Hassanain HH, Goldschmidt-Clermont PJ, Kovacic H,. 2003. Feedback by TSP2 regulates cell proliferation induced by Rac1 redox-dependent signaling. Mol Cell Biol. Vol. 23, no. 15: 5401-5408.

Lopes, Neuza; Gregg, David; Vasudevan, Sanjay; Hassanain, Hamdy; Goldschmidt-Clermont, Pascal; Kovacic, Herve. 2003. Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling. Molecular and Cellular Biology. Vol. 23, no. 15: 5401-5408.

Sundaram, U., Hassanain, H., Suntres, Z., Yu, J.G., Cooke, H.J., and Christofi, H.L. 2003. Rabbit chronic ileitis leads to up-regulation of adenosine A1/A3 gene products, oxidative stress, and immune modulation. Biochemical Pharmacology. Vol. 65, no. 9: 1529-1538.

Chen, Y., Liu-Stratton, Y., Hassanain, H., Cool, D.R., and Morris, M. 2004. Dietary sodium regulates angiotensin AT1a and AT1b mRNA expression in mouse brain. Experimental Neurology. Vol. 188, no. 2: 238-245.

Hassanain, H., Irshaid, F, Krishna, S., Al-kheraije KA, Wisel, S., Sheridan, J., Michler, R.E. and Goldschmidt-Clermont PJ. 2005. Smooth muscle cell expression of a constitutive active form of human Rac 1 accelerates wound repair. Surgery. Vol. 137, no. 1: 92-101.

Guzman J, Yu JG, Suntres Z, Bozarov A, Cooke H, Javed N, Auer H, Palatini J, Hassanain HH, Cardounel AJ, Javed A, Grants I, Wunderlich JE, Christofi FL. 2006. ADOA3R as a Therapeutic Target in Experimental Colitis. Inflamm Bowel Dis. Vol. Aug 12, no. 8: 766-789.

Hassanain, H., Gregg, D., Marcelo, Zweier, J. L., Souza, H.P., Selvakumar, B., Ma, Q, Moustafa-Bayumi, M., Binkley, P.F., Flavahan N.A., Morris, M., Dong, C., and Goldschmidt-Clermont, P. 2007. Hypertension caused by transgenic over-expression of Rac 1. Antioxidant and Redox Signaling. Vol. 9, no. 1: 91-100.

Chen Z, Suntres Z, Palmer J, Guzman J, Javed A, Xue J, Yu JG, Cooke HJ, Awad H, Hassanain HH, Cardounel AJ, Christofi FL. 2007. Cyclic AMP signaling contributes to neural plasticity and hyperexcitability in AH sensory neurons following intestinal Trichinella spiralis-induced inflammation. Int J Parasitol. Vol. 37, no. 7. (June): 743-761.

Moustafa-Bayoumi M, Alhaj MA, El-Sayed O, Wisel S, Chotani MA, Abouelnaga ZA, Hassona MD, Rigatto K, Morris M, Nuovo G, Zweier JL, Goldschmidt-Clermont P, Hassanain H. 2007. Vascular hypertrophy and hypertension caused by transgenic overexpression of profilin 1. J Biol Chem. Vol. 282, no. 52. (December 28): 37632-37639.

Positions

1979 - 1982

Instructor, Alexandria University, Genetics. Alexandria, Egypt.

1982 - 1984

Graduate Research Assistant, University of Illinois, Department of Microbiology. Urbana-Champaign, IL, United States.

1984 - 1985

Graduate Teaching Assistantship, Michigan State University, Department of Zoology. East Lansing, MI, United States.

1985 - 1986

Graduate Research Fellowship, University of Michigan, Department of Cellular and Molecular Biology. Ann Arbor, MI, United States.

1986 - 1989

Graduate Research Assistant, Michigan State University, Department of Zoology. East Lansing, MI, United States.

1990 - 1992

Postdoctoral Scientist, Hipple Cancer Research Center, Oncology. Dayton, OH, United States.

1992 - 1995

Faculty Research Associate, Hipple Cancer Research Center, Oncology. Dayton, OH, United States.

1995 - 1997

Research Scientist, The Ohio State University Medical Center, Medicine, Department of Internal Medicine. Columbus, OH, United States.

1997 - 2000

Adjunct Assistant Professor / Research Scientist, The Ohio State University Medical Center, Medicine, Department of Internal Medicine and Heart and Lung Research Institute. Columbus, OH, United States.

2000 - 2003

Adjunct Assistant Professor / Research Scientist, The Ohio State University Medical Center, Medicine, Division of Cardiothoracic Surgery, Department of Surgery, and Heart and Lung Research Institute. Columbus, OH, United States.

2004 - present

Assistant Professor (Tenure Track), The Ohio State University Medical Center, Medicine, Department of Anesthesiology and Heart and Lung Research Institute. Columbus, OH, United States.

2004 - present

Adjunct Assistant Professor of Surgery, The Ohio State University Medical Center, Medicine, Department of Anesthesiology and Heart and Lung Research Institute. Columbus, OH, United States.

Potential Publications Under Review

Hassan Talukder MA, Awad MM, Zweier JL, Abouelnaga ZA, Yang F, Nishijima Y, El-Sayed O, Hassona MDH, Alhaj MA, Khan M, Velayutham M, Moustafa-Bayoumi M, Goldschmidt-Clermont P, Hassanain HH. 2009. Overexpression of the active form of Zea maize RacD in the heart of a mouse model increases the susceptibility to postischemic contractile dysfunction and myocardial infarction. J Biological Chemistry. [Peer Reviewed] (First submission)

Moustafa-Bayoumi M, Kirby TE, Devor ST, Hassanain HH. 2009. Cardiac Responses to Endurance Training in a Dog Model of Healed Myocardial Infarction. Am J Physiol. [Peer Reviewed] (First submission)

Moustafa-Bayoumi M., Reiser P.J., Devor S.T., Kirby T.E., Hassanain H.H. 2009. Skeletal Muscle Myosin Heavy Chain Isoform and Calcineurin Signaling: Effect of Endurance Training. Am J Physiol. [Peer Reviewed] (First submission)

Presentations

Invited Presentations

Local

HH Hassanain, Presenter. 2006. Profilin and Rac1 genes in cardiovascular diseases. Presented at Research in Progress Seminar - Miller School of Medicine, University of Miami. (October 19)

Hamdy Hassanain, Presenter. 2007. Oxidative Stress and Cardiovascular Diseases: Insights from Transgenic Models. Presented at Dept of Anesthesiology Special Research In Progress Meeting, to Faculty, staff, medical students. 518 James Cancer Hospital. Columbus, OH, USA. (January 11)

Other Presentations

Local

HH Hassanain, Presenter. 2003. Role of Rac gene in cardiovascular research; insights from transgenic mice. Presented at Research in Progress Seminar - Heart and Lung Research Institute. (June 27)

HH Hassanain, Presenter. 2005. The role of Rac1 in wound healing. Presented at Research Day for the Division of Cardiothoracic Surgery. (May 5)

HH Hassanain, Presenter. 2007. The role of Rac1 in hypertension. Presented at Department of Anesthesiology - Research Seminar. (March 25)

ScipioP, Sun G, Alhaj M, Christofi F, Awad H, Hassanain H. 2007. The Role of C-Reactive Protein (CRP) in Atherosclerosis Causal Link or Simple Association? Presented at The Ohio State University Research Day. (March 28)

HH Hassanain, Presenter. 2007. Profilin and cardiovascular hypertrophy. Presented at Department of Anesthesiology - Research Seminar. (November 9)

HH Hassanain, Presenter. 2008. Profilin, vascular remodeling, and hypertension - role of integrins. Presented at Department of Anesthesiology - Research Seminar. (May 29)

Research Interests

AREAS OF RESEARCH

Project: 1

Transgenic Smooth Muscle Cell Expression of an Activated Rac Mutant Induces Hypertension
Hypertension represents a major risk factor for cardiovascular events such as stroke and myocardial infarction. It is established that both genetic and environmental factors contribute to the disease process. A balancing act between the renin/angiotensin/aldosterone system and cyclic GMP signaling pathways is mainly responsible for the maintenance of physiological blood pressures.

An important pathway for control blood pressure is activated by angiotensin II and recruits a vascular NADPH oxidase activity. In the pathway activated by ang-II, as well as for any putative pathway that requires the production of superoxide (.O2-) by NADPH oxidase to induce hypertension, the final common step is the switching on of the small guanyl binding protein Rac. Rac 1 is a small GTP-binding protein of the Ras superfamily, which regulates a wide variety of cellular activities including the activity of NADPH oxidase. Rac 1 activation is mediated by the exchange of the GDP bound to inactive Rac for GTP. It has been shown recently that angiotensin II induced upregulation of Rac 1 gene mediated free radicals. Although activated Rac could regulate the activity of several effector enzymes beside NAD(P)H oxidase, such as p21-activated kinase (PAK), p70 S6 kinase, PI3-kinase and other lipid kinases, and could affect scaffold proteins like Posh and POR-1, our data support the hypothesis that the impact of Rac CA on blood pressure involves its agonistic effect on vascular NAD(P)H oxidase.

Superoxide (.O2-) is a potent vasoconstrictor substance that modulates the vascular tone. In order to alter the impact of superoxide on the vascular tone, we have expressed transgenically the cDNA of a constitutively active mutant of human Rac 1 (Rac CA), or the dominant negative isoform (Rac DN) in the blood vessels of transgenic FVB/N mice using mouse vascular smooth muscle -actin promoter. We have monitored the blood pressure of Rac CA, Rac DN transgenic mice and of non-transgenic controls. Our results showed that overexpression of Rac CA in the blood vessels induced a chronic hypertensive response in Rac CA mice as compared to the nontransgenic littermates. However, there was no significant difference between the mean arterial pressure (MAP) between Rac DN and nontransgenic controls.

Myogenic analysis of small arteries (arterioles) showed a marked reduction in the myogenic response in Rac DN and great increase in myogenic propose in Rac CA mice which could contribute to the elevated mean arterial pressure in these mice. Furthermore, Rac CA overexpression increased the production of peroxynitrate with consequent increased nitration of proteins in transgenic vessels. There was no change in eNOS expression in Rac CA mice compared to nontransgenic, and renin activity was decreased in Rac CA transgenic mice as compared to controls. Echocardiographic results showed, that hypertension in these transgenic mice was associated with left ventricular hypertrophy (LVH). Moreover, Rac CA induced hypertension could be corrected with an antioxidant such as N-acetylcysteine (NAC).


Project: 2

Cardiac Overexpression of a Constitutive Active Form of Zea maize Rac D in Transgenic Mice Deteriorates Postischemic Contractile Recovery
Myocardial damage caused by ischemia/reperfusion (I/R) injury remains a major concern and a leading cause of cardiovascular death. Reactive Oxygen Species (ROS) play a critical role in I/R. A potential source of myocardial ROS is NADPH oxidase, which is regulated by the small GTP-binding protein Rac1. Our previous study showed that the structure of the Rac gene, as it relates to the ability of Rac to induce production of superoxide, has been highly conserved throughout evolution, such that a maize Rac gene product is capable of regulating the generation of superoxide in mammalian cells. In addition, the maize Rac D gene produced the highest levels of superoxide when expressed in a mammalian system as compared to the human Rac1 gene. In order to study the effect of increased ROS in the heart on I/R, we have transgenically expressed the cDNA of a constitutively active mutant of Zea Maize Rac D gene in the heart of transgenic FVB/N mice using a mouse -myosin heavy chain promoter. Electron paramagnetic resonance (EPR) showed increased ROS production in the hearts of Rac D transgenic mice compared to controls. H&E and trichrome staining showed significant myocardial damage and replacement fibrosis, particularly in left atrium. Echocardiographic analysis clearly showed dilation in the hearts of transgenic mice and significantly low ejection fraction of 20% in transgenic mice compared to 62% (p less than 0.05) in controls. Hearts isolated and perfused on Langendorff mode for I/R studies demonstrated markedly poor post-ischemic contractile recovery (48 +/- 4%) compared to WT hearts (95 +/- 4%). We are using this model in collaboration with Dr. Zweier to assess the role of Rac 1 gene in ischemia/reperfusion injury.

Project 3:

The Role of Profilin in vascular smooth muscle contractility and hypertension in a transgenic mouse model
The ubiquitous G-actin binding protein profilin is believed to be a key regulator of actin polymerization in cells. Profilin promotes actin assembly from G-actin pool into the polymerized form (F-actin). In order to assess the role of actin polymerization on vascular function, we have overexpressed transgenically either the wild-type cDNA of a human profilin gene (WT), or the dominant negative mutant isoform (88R/L) in the blood vessels of transgenic FVB/N mice using VSMP8 mouse vascular smooth muscle -actin promoter. Transgenic mice were identified by PCR analysis of tail genomic DNA using specific primers that selectively recognize the transgene. RT-PCR analysis confirmed the selective transcription of profilin in smooth muscle, including blood vessels, spleen and intestine, while the transgene transcript was not detected in control mice. Histological analysis on aorta from WT-profilin, 88R/L mutant and nontransgenic for actin polymerization using rhodamine staining showed that actin polymerization was high in WT-profilin transgenic, low in nontransgenic and lowest in 88R/L transgenic mice. We have assessed the migration profile of vascular smooth muscle cells (VSMCs) isolated from aorta of transgenic or nontransgenic mice. We found that VSMCs cells from WT-profilin migrate faster than those from 88R/L or nontransgenic controls.

We also have monitored the blood pressure of WT-profilin and of nontransgenic controls. Our results showed that overexpression of WT-profilin in smooth muscle cells induced a chronic hypertensive response in these mice as compared to the nontransgenic. Conclusion: Increased actin polymerization in WT-profilin transgenic mice may increase vasoconstriction of the blood vessels that leads to elevated mean arterial pressure. This model represents a foundation to further explore the potential effects of actin cytoskeleton in hypertension.


Project: 4

(The Ph.D. thesis project for Moustafa Bayuime in collaboration with Dr. George Billman).

Endurance Training Reversed Canine Susceptibility to Lethal Arrhythmias: NOS as Potential Mediators
Sudden cardiac death (SCD) is the leading cause of death in industrial countries accounting for approximately one third of all deaths among men aged 20 to 64 years. In the United States 400,000 to 450,000 men died suddenly per year from 1989 to 1998. Holter analysis revealed that ventricular tachyarrhythmias that culminate in ventricular fibrillation (VF) account for the vast majority (75-93%) of SCD cases. The very low percentage (~ 1%) of cardiac arrest victims who are resuscitated and survive to leave the hospital emphasize the vital risk of VF and highlight the crucial need to identify the underlying mechanisms responsible for these malignant arrhythmias so that effective preventive interventions can be developed.

Disturbances in cardiac autonomic balance play a critical role in triggering lethal rhythm disturbances. Increased cardiac sympathetic activity promotes VF while enhanced parasympathetic activity antagonizes it. Both experimental and clinical studies demonstrate that during recovery from myocardial infarction, individuals with the greatest reduction in cardiac vagal activity coupled with increased sympathetic activity have the greatest risk for sudden death.

Interventions that reduce sympathetic activity and/or increase parasympathetic activity should protect against VF. It is well established that endurance training can alter cardiac autonomic balance by both increasing parasympathetic tone and decreasing sympathetic activity. In cardiac patients, aerobic exercise training leads to a decrease in sympathetic activity and an increase in parasympathetic activity and baroreflex sensitivity (BRS). In addition, daily exercise may prevent ischemically induced VF in a canine model of sudden death.

Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and has been shown that it may act at the pre-synaptic level to facilitate vagal bradycardia via a cGMP-dependent mechanism. In both mice and guinea pigs, exercise training up-regulates nNOS and this up-regulation results in increased vagal responsiveness in trained animals compared to sedentary controls.

Therefore, aerobic training may protect from VF. However, neither the effectiveness of endurance training in reversing the susceptibility to VF nor the molecular mechanism mediating this protective effect has been investigated, especially in large animals (i.e. dogs). The general aim of this study was to assess the effectiveness of endurance training in reversing the susceptibility to VF in a canine model of sudden death and investigate the role of nitric oxide (NO) as a potential mediator for this protection effect.

Project:5

Role of C-reactive protein in atherosclerosis: Clinical outcomes from vascular surgery patients and transgenic mouse model
Principal Investigator: Hamdy Awad, M.D., Anesthesiology
Co-Principal Investigators: Richard Mortensen, Ph.D., Prof. of Microbiology; Hamdy H. Hassanain, Ph.D., Assist. Prof.,Surgery & DHLI; Fievos L. Christofi, Ph.D., Vice Chair of Research, Anesthesiology; Zach Suntres, Ph.D. DR-DC, Canada; William L. Smead, Ph.D., Prof. Surgery, James C. Tober, MD, Assoc. Professor of Surgery; Stacy Hoshaw – Woodard (Statistician); Medical student Fellow: Mr. Bryan Wolfe.

Atherosclerosis leads to pain and disability as well as a 6-fold increase in the risk of developing potentially fatal cardiovascular disease, affecting almost 20 million people in the U.S. Atherosclerotic plaques form as fatty streaks which develop into atheromas; further progression and destabilization results in plaque rupture and occlusive thrombosis. Thrombotic diseases including myocardial infarction, stroke, peripheral occlusive arterial disease and pulmonary embolism result in ~1 million deaths each year. Stroke and peripheral occlusive arterial disease also contribute strongly to permanent disability as a result of paralysis and limb loss. Atherosclerosis is a main underlying cause of carotid occlusion requiring endarterectomy to prevent stroke or sudden death and chronic arterial occlusive disease of lower extremities leading to a dysfunctional painful limb. A further understanding of atherogenesis and the formation of atherosclerotic plaque is essential in developing improved therapies able to prevent its progression. Arterial inflammation has emerged as the central mechanism to the progression of atherosclerosis. CRP serves as a marker of inflammation and predicts risk of adverse cardiovascular events resulting from atherosclerosis. Uptake of CRP-opsonized native LDL-cholesterol by macrophages may contribute to foam cell formation. The presence of CRP receptors on monocytes may aid in local monocyte recruitment into the intima.

However, it remains unknown whether CRP is involved or contributes to the development of atherosclerotic lesions. Our proposal is an outcome study on CRP both in patients with vascular disease and transgenic mice overexpressing homologous CRP to investigate its role in atherogenesis or atherosclerosis. Clinical outcomes include measures of morbidity, mortality and CRP, IL-1β, IL-6 and TNFα levels in blood of patients with vascular diseases and in atherosclerotic plaques excised from endarterectomy patients. A mouse model of CRP overexpression (see section C) will be used to assess these parameters and their role in the development of atherosclerotic plaques in combination with two other high risk factors: high fat diet and age. Data from the CRP mouse model in combination with clinical outcomes will provide fundamental insights into the cause – effect relationship between CRP and atherogenesis or atherosclerosis. This is also essential in the interpretation of the plethora of clinical outcome data that merely provide an association between CRP and atherosclerosis. A positive outcome in the mouse model would provide a rational basis for developing therapeutic interventions that are specific for CRP, as opposed to current therapy.


Project: 6

Purine receptors in atherosclerotic plaque: Insights from carotid artery atheroma and transgenic mouse model of peripheral vascular disease
Principal Investigator: Fievos L. Christofi, Ph.D., Vice Chair of Research, Anesthesiology
Co-Principal Investigators: Hamdy E. Awad, M.D., Assistant Prof. (Tenure Track), Anesthesiology; Gerrald De Nuovo, M.D., Prof. Pathology; Hamdy H. Hassanain, Ph.D., Assist. Prof.,Surgery; Zacharias Suntres, Ph.D., Research Scientist, DR-DC, Canada; William L. Smead, Ph.D., Prof. Surgery, James C. Tober, MD, Assoc. Professor of Surgery; Stacy Hoshaw – Woodard (Statistician)

Despite overwhelming evidence from hundreds of in vitro studies on human or animal cells indicating that purines and multiple nucleotide P2X and P2Y receptors activate all the cells involved in atherogenesis and formation of atherosclerotic plaques, there is no direct evidence for the expression and types of P2 receptors in human atherosclerotic plaque or in underlying and surrounding layers of cells close to the atheroma. Our study will provide direct evidence for the expression, distribution and types of P2 receptors present in atherosclerotic plaques in human carotid arteries from patients undergoing endarterectomy near carotid bifurcations. This would provide more rational therapeutic targeting of specific P2 purine receptors via P2 receptor antagonist drugs as recently proposed (Franscesco & Solini, 2002). In fact, clinical studies are already providing some encouraging results in preventing vascular accidents using ADP receptor/ P2Y antagonists against platelet aggregation) – platelets are only half a dozen cell types involved in plaque formation that express P2 receptors and the potential for identifying additional therapeutic targets is very high. A mouse transgenic model will provide specific data about the role and putative changes in P2 receptors during the vascular remodeling involved in the atheroma. Dr. Nuovo (Pathologist at OSU), a world expert and pioneer of in situ RT-PCR, will perform a detailed analysis of the distribution of P2X4, P2X7, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11,P2Y12 receptor mRNAs in plaque and vessel wall layers in specimens excised from patients undergoing endarterectomy – primers used are in routine use in our lab for analysis of mRNAs in other human cells. P2X and P2Y receptors will be analyzed and characterized by 3-Dimensional reconstruction of P2 mRNA distribution, immunofluorescent localization via laser confocal imaging, immunoblot analysis, and in vivo ATP detection in blood in the vicinity of the atherosclerotic plaque during endarterectomy. Comparisons in P2 mRNAs between arterial vessel wall layers in post-mortem patients without any vascular disease and those with atherosclerosis will provide critical information about alteration in the expression of particular P2 receptor subtypes in the progression of the disease. Vascular remodeling in the vessel wall is of pivotal importance in the formation of atherosclerotic plaque. Fortuitously, Dr. Hassanain (Co-PI) has recently succeeded in developing a “transgenic mouse model of vascular remodeling” that will be used to provide unequivocal proof for alterations in P2 receptor subtypes. Feeding a subset of transgenic animals with a high fat diet may lead to atherosclerosis and thereby further permit specific receptor changes in the disease process to be identified. The long-term goal of this new research initiative is to seek external funding from NIH on the functional relevance of P2 receptors in atherosclerotic plaque formation, and design and testing of new P2 receptor antagonist drugs to interfere with the progression of atherosclerosis. Purine research has been the focus of the PI’s lab over the past 13 years, which is currently supported by 3 NIH grants and an NIH fellowship in this field (as PI/Co-PI).

I have conducted a molecular program in vascular biology and engineered a series of transgenic mice to study cardiovascular diseases. These are novel models which have led to breakthroughs in the field of cardiovascular disease such as hypertension, Diabetes, vascular remodeling and heart failure.

In January 2007, we were the first to report the role of Rac1 gene in the development of hypertension (ARS, 2007). In addition, I have discovered a new gene that leads to vascular remodeling and subsequently increase high blood pressure by the time the mice are 6 months old – the rough equivalent to middle age in humans (JBC 2007). Therefore, this recent finding might lead to new therapeutic options for high blood pressure, especially hypertension associated with aging. Furthermore, the Rac1 transgenic model that I developed in my laboratory led us to discover treatment for Kaposi Sarcoma in collaboration with Miami University Medical center. Our future goals are to apply what we discovered in animal models to the humans, therefore we are in the process of submitting two IRBs for that purpose.


RESEARCH COLLABORATION

Pascal J. Goldschmidt-Clermont, MD.
Dean of Miami University Medical School
Collaboration: “Free radicals and cardiovascular diseases”

Jay Zweier, M.D.
Professor and Chief of cardiology and Director of EPR Center
Johns Hopkins University.
Collaboration: “Assessments of the redox state in the aortas and hearts of hypertensive/ hypotensive mouse models”

Fievos L Christofi, Ph.D.
Professor of Anesthesiology and Vice Chair of Research
The Ohio State University
Collaboration: “Structural and functional remodeling of resistance arteries in Rac CA hypertensive and Rac DN hypotensive mice” , “ The regulation of adenosine receptors expression during inflammation”, “The role of .O2- anions in GI function“ and “Plasticity of adenosine receptors in Rac CA transgenic mice“

Mariana Morris, Ph.D.
Professor and Chair of Pharmacology and Toxicology
Wright State University, Dayton Ohio
Collaboration: “Assessment of the circadian blood pressure in Rac CA hypertensive and Rac DN hypotensive mice and the determine the effects of vasoactive agents in the blood pressure”.

Phillip F. Binkley, M.D.
Professor of Medicine and Head of Heart failure Transplantation Section.
Division of Cardiology and Heart and Lung Research Institute
The Ohio State University.
Collaboration: “Signaling cascades of cardiac hypertrophy in Rac CA transgenic mice”

Gerard J. Nuovo, M.D.
Associate Professor of Medicine
Division of Pathology
The Ohio State University
Collaboration: “In Situ RT-PCR”

Arthur R. Strauch, Ph.D.
Professor of Cell Biology and Physiology
Department of physiology and Heart and Lung Research Institute
The Ohio State University.
Collaboration: “Myofibroblasts and wound healing”

John Bauer, Ph.D.
Associate Professor of Pharmacology
The Ohio State University
Collaboration: “Oxidative stress and bladder dysfunction and remodeling”

Robert Hamlin, DVM
Professor of Veterinary Bioscience
Department of Veterinary Medicine
The Ohio State University.
Collaboration: “Profilin and vascular hypertrophy”

Brad Rovin, M.D.
Professor of Medicine
Department of Nephrology and HLRI
The Ohio State University.
Collaboration: “Oxidative stress and kidney dysfunction in Rac CA hypertensive mice”.

Rhian Touyz, M.D.
Assistant Professor of medicine
Clinical Research Institute of Montreal
University of Montreal, Quebec, Canada.
Collaboration: “Assessment of the myogenic response in transgenic mice suffering from vascular hypertrophy”.

Undergrad., Grad. and Prof. Courses Taught

2007. The Ohio State University, Microbiology. Independent Studies 699, 2007-pres 699. 5 credit hours

Autumn 2008. The Ohio State University, Near Eastern Studies. Arabic 101.01 101.01. 5 credit hours