Vice Dean for Research, Joan C. Edwards School of Medicine
Department: Pharmacology, Physiology and Toxicology
Research Cluster: Cardiovascular Disease, Obesity, and Diabetes
Office: MU Medical Center, Administrative Suite
Lab: MU Forensic Science Center
Phone: (304) 691-1791
Research projects in Dr. Abraham’s laboratory funded by NIH, focus on vascular dysfunction which is a prelude to obesity and cardiovascular disease including hypertension, stroke, and diabetes. Heme oxygenase (HO)-1 is the enzyme in humans that degrades heme in the spleen to generate iron (iron utilization), carbon monoxide (CO) and bilirubin (antioxidant). The research focuses on how the HO-1 (the most potent anti-oxidant gene in the human body)-adiponectin-EET module play an essential role in vascular function. We believe that HO-1 acts as a molecular “switch” to genetically reprogram stem cells and, subsequently, vascular endothelium through activation of a unique signaling cascade that results in the amplification of protective circuits that provide resistance to vascular dysfunction. Increased HO-1 expression provides protection for stem cell function and bone formation and, also, decreases adiposity. HO-1 also serves as the mediator of cross-talk between adipose tissue and the vasculature. Our studies focus on the impact of adipocyte stem cell dysfunction on vascular endothelial integrity through the role of HO-1. HO-1 expression in epicardial tissue provides protection to heart function and attenuates myocardial infarction (MI) and heart failure. Both human and animal models of diabetes and obesity are utilized to examine the use of stem cell intervention and gene therapy to amplify HO-1 levels. Additionally, our research approach is a powerful tool in the identification of therapeutic strategies and novel biomarkers for cardiovascular and metabolic disease (e.g. circulating endothelial cells and progenitor stem cells [EPCs] for better prognosis). We believe that the effect of anti-diabetic drugs alone, or in combination with antioxidant genes, has a differential impact on stem cell function and vascular disease as well as on stem cell differentiation into adipocytes and osteoblasts. The genomic approach and gene array analysis described in various publications from our laboratory represents a powerful tool to systematically investigate therapeutic approaches and, thus facilitate translational research in hypertension, diabetes and the metabolic syndrome using stem cells and / or gene therapy. Additionally, our laboratory is focusing on the identification of biomarkers as diagnostic tools for monitoring the progression of several genetic diseases in order to predict future pathophysiological conditions and the potential use of cell therapy for disease prevention. Dr. Abraham’s group is collaborating with Dr. Kathleen O’Hanlon (Family Medicine), Drs. Ellen Thompson and Robert Touchon (Cardiology) and Ryan Stone (OB/GYN) and Dr. Zeid Khitan (Chief, Nephrology) and Dr. Yoram Elitsur (Pediatrics) to identify blood biomarkers for disease progression.
For a full listing of publications, please access PubMed.
Selected Publications to Scheme 1
Pharmacological and Clinical Aspects of Heme Oxygenase. Abraham NG and Attallah Kappas. Pharmacological Reviews, March 2008 Mar;60(1):79-127. The most cited and visited pharmacological paper in 2009 (Thomson Reuters).
Heme oxygenase-1 gene expression modulates angiotensin II-induced increase in blood pressure. Yang L, Quan S, Nasjletti A, Laniado-Schwartzman M, Abraham NG. Hypertension 43:1221-1226,2004.
Human heme oxygenase-1 gene transfer lowers blood pressure and promotes growth in spontaneously hypertensive rats. Sabaawy HE, Zhang F, Nguyen X, El Hosseiny A, Nasjletti A., Schwartzman M., Dennery, P, Kappas A, Abraham NG. Hypertension 38:210-215, 2001.
Effect of heme arginate administration on blood pressure in spontaneous hypertensive rats. Levere RD, Martasek P, Escalante B, Schwartzman ML, Abraham NG. J. Clin. Invest. 86:213-219, 1990.
Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin. Chernick RJ, Martasek P, Levere RD, Margreiter R, Abraham NG. Hepatology 10(3):365-369, 1989.
Selected Publications to Scheme 2
The stem-cell mavens had a blast – review of the Second International Symposium on Molecular Biology of Hematopoiesis. Abraham NG, Benz EJ, Karlsson S, Lutton JD, Clark SC. The New Biologist 4(1):1-4, 1992.
Molecular regulation – biological role of heme in hematopoiesis. Abraham NG. Blood Reviews 5:1-10, 1991.
Transcriptional modulation of heme oxygenase expression in bone marrow stroma. Abraham NG, Lavrovsky Y, Harrison JS, Staudinger R. Blood 82(10):19a, 1993.
Identification and purification of mesodermal progenitor cells from human adult bone marrow. Petrini N, Pacini S, Trombi , Fazzi R, Montali M, Ikehara S, Abraham NG. (2009) Stem Cells Dev, Jul-Aug, 2009 18(6): 857-866.
Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats. Nicolai A, Li M, Kim DH, Peterson SJ, Vanella L, Positano V, Gastaldelli A, Rezzani R, Rodella LF, Drummond G, Kusmic C, L’Abbate A, Kappas A and Abraham NG (2009) Hypertension 2009 Mar;53(3): 508-515. Epub Jan 26.
Adipocyte heme oxygenase-1induction attenuates metabolic syndrome in both male and female obese mice.Burgess A, Li M, Vanella L, Kim DH, Rezzani R, Rodella L, Sodhi K, Canestraro M, Martasek P, Peterson SJ, Kappas A, Abraham NG. Hypertension. 2010 Dec;56(6):1124-30. Epub 2010 Nov 1. PMID: 21041703; PMCID: PMC3031103
Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet. Cao J, Peterson SJ, Sodhi K, Vanella L, Barbagallo I, Rodella LF, Schwartzman ML, Abraham NG, Kappas A. Hypertension.2012 Aug;60(2):467-75. Epub 2012 Jul 2. PubMed PMID: 22753217
Selected Publications to Scheme 3
Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept. Kusmic C, Barsanti C, Matteucci M, Vesentini N, Pelosi G, Abraham NG, L Abbate A. J Transl Med. 2014 Apr 5;12(1):89. PMID:24708733
Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative Stress. Issan Y, Kornowski R, Aravot D, Shainberg A, Laniado-Schwartzman M, Sodhi K, Abraham NG, Hochhauser E. PLoS One. 2014 Mar 21;9(3):e92246. PMID:24658657
Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Hinds TD Jr, Sodhi K, Meadows
C, Fedorova L, Puri N, Kim DH, Peterson SJ, Shapiro J, Abraham NG, Kappas A. Obesity (Silver Spring). 2014 Mar;22(3):705-12. PMID:23839791
HO-1 induction improves the type-1 cardiorenal syndrome in mice with impaired angiotensin II-induced lymphocyte activation. Monu SR, Pesce P, Sodhi K, Boldrin M, Puri N, Fedorova L, Sacerdoti D, Peterson SJ, Abraham NG, Kappas A.Hypertension. 2013 Aug;62(2):310-6. PMID:23753410
Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade.Vanella L, Sodhi K, Kim DH, Puri N, Maheshwari M, Hinds TD Jr, Bellner L, Goldstein D, Peterson SJ, Shapiro JI, Abraham NG. Stem Cell Res Ther. 2013 Mar 12;4(2):28. PMID: 23497794
Improved Expression of Sirt1 on Thymic Epithelial Cells of SAMP10 after Intra Bone Marrow-Bone Marrow Transplantation. Li M, Shi M, Abraham NG, Ikehara S. Cell Transplant. 2013 Feb 26. PMID:23452762
Heme oxygenase-2/adiponectin protein-protein interaction in metabolic syndrome.Vanella L, Li Volti G, Guccione S, Rappazzo G, Salvo E, Pappalardo M, Forte S, Schwartzman ML, Abraham NG. Biochem Biophys Res Commun. 2013 Mar 22;432(4):606-11. PMID: 23438433
Effects of heme oxygenase-1 upregulation on blood pressure and cardiac function in an animal model of hypertensive myocardial infarction. Chen TM, Li J, Liu L, Fan L, Li XY, Wang YT, Abraham NG, Cao J. Int J Mol Sci. 2013 Jan 28;14(2):2684-706. PMID:23358254
Cyclooxygenase-2 dependent metabolism of 20-HETE increases adiposity and adipocyte enlargement in mesenchymal stem cell-derived adipocytes. Kim DH, Puri N, Sodhi K, Falck JR, Abraham NG, Shapiro J, Schwartzman ML. J Lipid Res. 2013 Mar;54(3):786-93. doi: 10.1194/jlr.M033894. Epub 2013 Jan 4. PMID:23293373
Elevated level of pro-inflammatory eicosanoids and EPC dysfunction in diabetic patients with cardiac ischemia. Issan Y, Hochhauser E, Guo A, Gotlinger KH, Kornowski R, Leshem-Lev D, Lev E, Porat E, Snir E, Thompson CI, Abraham NG, Laniado-Schwartzman M. Prostaglandins Other Lipid Mediat. 2013 Jan;100-101:15-21. PMID:23291334
The emerging role of heme oxygenase and its metabolites in the regulation of cardiovascular function. Stec DE, Ishikawa K, Sacerdoti D, Abraham NG. Int J Hypertens. 2012;2012:593530. PMID:23133743
Antioxidants condition pleiotropic vascular responses to exogenous H(2)O(2): role of modulation of vascular TP receptors and the heme oxygenase system. Puri N, Zhang F, Monu SR, Sodhi K, Bellner L, Lamon BD, Zhang Y, Abraham NG, Nasjletti A. Antioxid Redox Signal. 2013 Feb 10;18(5):471-80. PMID: 22867102
Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet. Cao J, Peterson SJ, Sodhi K, Vanella L, Barbagallo I, Rodella LF, Schwartzman ML, Abraham NG, Kappas A.Hypertension. 2012 Aug;60(2):467-75.PMID: 22753217
12(R)Hydroxytetranoic acid, a cytochrome P450-dependent arachidonate metabolite that inhibits Na+-K+-ATPase in the cornea. Schwartzman ML, Balazy M, Masferrer J, Abraham NG, McGiff JC, Murphy RC. Proc. Natl. Acad. Sci. USA 84:8125-8129, 1987.
CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid-and angiotensin II-dependent. Sodhi K, Wu CC, Cheng J, Gotlinger K, Inoue K, Goli M, Falck JR, Abraham NG, Schwartzman ML. Hypertension. 2010 Nov;56(5):871-8. Epub 2010 Sep 13. PubMed PMID: 20837888; PMCID: PMC2995375
Selected Publications to Scheme 4
Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats. Sacerdoti D, Escalante B, Abraham NG, McGiff JC, Levere RD, Schwartzman ML. Science 243:388-390, 1989.
Hemin and L-arginine regulation of blood pressure in spontaneous hypertensive rats. Martasek P, Schwartzman ML, Goodman AI, Solangi K, Levere RD, Abraham NG. J. Amer. Soc. Nephrol. 2(6):1078-1084, 1991.
Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: Protective effect against heme and hemoglobin toxicity. Abraham NG, Lavrovsky Y, Schwartzman ML, Stoltz RA, Levere RD, Gerritsen, E., Shibahara, S. and Kappas, A. Proc. Natl. Acad. Sci. USA 92:6798-6802, 1995.
Heme oxygenase-1 attentuates glucose mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Abraham N.G., Kushida T, McClung J, Quan S, Kafaro R, Darzynkiewicz Z, and Wolin MS. Circ Res 2003;93: 131-9
D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing and improves vascular reactivity in a rat model of diabetes. Kruger AL, Peterson S, Turkseven S, Kaminski PM, Zhang, Quan S, Wolin MS, Nader Abraham NG. Circulation, June 14;111(23):3126-34, 2005.
Diabetes Impairs the Vascular Recruitment of Normal Stem Cells by Oxidant Damage; Reversed by Increases in pAMPK, Heme Oxygenase-1 and Adiponectin. Sambuceti G, Morbelli S, Vanella L, Kusmic C, Marini C, Massollo M, Augeri C, Corselli M, Ghersi C, Chiavarina B, Rodella LF, L’Abbate A, Drummond G, Abraham NG and Frassoni F (2009) . Stem Cells. 2009 Feb;27(2): 399-407.
Endothelial Progenitor Cell Function Inversely Correlates With Long-term Glucose Control in Diabetic Patients: Association With the Attenuation of the Heme Oxygenase-Adiponectin Axis.Issan Y, Hochhauser E, Kornowski R, Leshem-Lev D, Lev E, Sharoni R, Vanella L, Puri N, Laniado-Schwartzman M, Abraham NG, Porat E. Can J Cardiol. 2012 Mar 23. [Epub ahead of print] PubMed PMID: 22445099
Usefulness of clopidogrel to protect against diabetes-induced vascular damage.McClung JA, Kruger AL, Ferraris A, Vanella L, Tsenovoy P, Weiss MB, Abraham NG, Am J Cardiol. 2010 Apr 1;105(7):1014-8.
Elevated level of pro-inflammatory eicosanoids and EPC dysfunction in diabetic patients with cardiac ischemia. Issan Y, Hochhauser E, Guo A, Gotlinger KH, Kornowski R, Leshem-Lev D, Lev E, Porat E, Snir E, Thompson CI, Abraham NG, Laniado-Schwartzman M. . Prostaglandins Other Lipid Mediat. 2013 Jan;100-101C:15-21. doi: 10.1016/j.prostaglandins.2012.12.002. Epub 2013 Jan 3. PubMed PMID: 23291334
Lentiviral-Human Heme Oxygenase Targeting Endothelium Improved Vascular Function In Ang II Animal Model of Hypertension. Cao, J., Sodhi, K., Inoue, K., Quilley, J., Rezzani, R., Rodella, L., Vanella, L., Germinario, L., Stec, D.E., Abraham, N.G., Kappas, A. Human Gene Therapy, 2011 Mar;22(3):271-82. PubMed PMID: 20836698; PubMed Central PMCID: PMC3057195