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Donald W. Jacobsen, Ph.D., F.A.H.A.Staff, Joint Appointment with Department of Cardiovascular Medicine
Department of Cell Biology |
Area of general research interest:
Cardiovascular disease, homocysteine metabolism, endothelial cell function, cobalamin and folate biochemistry
Current program:
- Homocysteine as a modifiable risk factor for cardiovascular disease.
- Vascular cell metabolism of homocysteine and gene-nutrient interactions.
- Homocysteine-induced gene expression in vascular cells.
- Vascular biochemistry of vitamin B12
Investigators:
- Armend Axhemi, M.S.
- Otilia Catanescu, Ph.D., Fellow
- Patricia DiBello, M.S., Principal Technoligist
- Alla V. Glushchenko, M.D., Ph.D., Fellow
- Luciana Hannibal, B.S.
- Edward Suarez-Moreira, B.S., Graduate Student
- Steve Schomisch, B.S.
Collaborators:
- Jean-Paul Achkar, M.D., Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH
- Richard C. Austin, Ph.D., Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Michael E. Ketterer, Ph.D., Department of Chemistry, Northern Arizona University, Flagstaff, AZ
- Michael T. Kinter, Ph.D., Department of Cell Biology, Lerner Research Institute, Cleveland OH
- Warren D. Kruger, Ph.D., Fox Chase Cancer Center, Philadelphia, PA
- Steven R. Lentz, M.D., Ph.D. Department of Internal Medicine, University of Iowa School of Medicine, Iowa City IA
- Andrew McCaddon, M.D., University of Wales College of Medicine, Wrexham, UK
- Alexander A. Zhloba, M.D., Department of Biochemistry, Pavlov Medical University, St Petersburg, Russia
Brief Description:
Our laboratory does clinical and basic research on the sulfur-containing amino acid homocysteine, an important new independent risk factor for cardiovascular disease. Homocysteine, a product of methionine metabolism, is cytotoxic to cells if allowed to accumulate. Hence, it is remethylated back to methionine, or is converted to cysteine by metabolism through the transsulfuration pathway. Impairment of homocysteine metabolism, caused either by genetic or acquired factors, can lead to higher intracellular concentrations and subsequent export to the blood. Hyperhomocysteinemia is a condition in which total plasma homocysteine (i.e., the sum of reduced and oxidized forms of homocysteine) exceeds 12 µM.
The incidence of hyperhomocysteinemia in patients with coronary artery disease at the Cleveland Clinic Foundation is 30-50%, depending on patient subset. These patients usually have mild hyperhomocysteinemia (>12-25 µM). Approximately 65% of the 180 heart transplant recipients we have studied have mild to intermediate hyperhomocysteinemia (>12-50 µM). Post-transplant hyperhomocysteinemia occurs within three months and by one year most of these patients have developed vasculopathies in their coronary arteries. We have also studied 200 dialysis patients with end-stage renal disease. Greater than 85% have hyperhomocysteinemia which is often severe (50-150 µM total plasma homocysteine). Associated with end-stage renal disease is a high incidence of cardiovascular disease. Because the incidence of hyperhomocysteinemia in patients with cardiovascular disease is high, we hypothesize that homocysteine is either causal or plays a role in disease progression.
We have determined that human aortic endothelial cells have a limited capacity to metabolize homocysteine. By direct enzyme assay and Western blotting, we have shown that the first enzyme in the transsulfuration pathway, namely cystathionine b-synthase, is not expressed. An alternate remethylation pathway enzyme betaine:homocysteine methyltransferase is also not expressed. The limited capacity to metabolize homocysteine, we hypothesize, makes the vascular endothelium particularly vulnerable to the elevated levels of circulating homocysteine seen in hyperhomocysteinemia. Exposure to elevated plasma homocysteine can cause endothelial cell dysfunction.
A normal function of endothelial cells is to recruit monocytes to sites of cellular injury or infection. At these or nearby sites endothelial cells become "activated" and express newly synthesized macromolecules such as cytokines and cellular adhesion molecules. Some of the cytokines serve as chemoattractants to lure monocytes to the surface of the vascular endothelium where they attach via their own cellular adhesion molecules and those expressed by endothelial cells. Once firmly attached monocytes can then transmigrate into the intimal space. These "inflammatory" like events also occur in atherogenesis, a process in which intimal monocytes become lipid-laden macrophages (foam cells). What role does homocysteine play in atherogenesis? In cultured human aortic endothelial cells, homocysteine induces expression of monocyte chemoattractant protein-1 (MCP-1) and interlukin 8 (Il-8), chemokines for the recruitment of monocytes and neutrophils, respectively. In addition to mRNA induction, homocysteine also triggers the release of MCP-1 and IL-8 protein. Induction and release is mediated by 5-50 µM L-homocysteine (the D enantiomer is inactive). L-cysteine is inactive suggesting that the mechanism is not due to a general thiol effect involving the generation of reactive oxygen species. Studies are underway to elucidate the mechanisms of homocysteine-induced chemokine expression and release.
Although homocysteine is a strong independent risk factor for cardiovascular disease, its precise role in atherogenesis and disease progression is unclear. However, in most individuals with hyperhomocysteinemia, it is possible to lower total plasma homocysteine concentrations to levels that are deemed free of risk (<=10 µM). We have completed homocysteine lowering studies in patents with coronary artery disease, in heart transplant recipients and in patients with end-stage renal disease. A combination of folic acid, cyanocobalamin and pyridoxine are effective in lowering homocysteine levels in patients with heart disease and in heart transplant recipients. Patients with kidney failure, on the other hand, are more difficult to treat and will require novel therapeutic approaches, which are under development in this laboratory.
Key References:
Targeting of Metallothionein by L-Homocysteine: A Novel Mechanism for Disruption of Zinc and Redox Homeostasis. J.C. Barbato, O. Catanescu, K. Murray, P.M. DiBello and D.W. Jacobsen (2007) Arterioscler Thromb Vas Biol 27:49-54.
X-ray Structural Characterization of Imidazolylcobalamin and Histidinylcobalamin: Cobalamin Models for Aquacobalamin Bound to the B12 Transporter Protein Transcobalamin. L. Hannibal, S.D. Bunge, R. van Eldik, D.W. Jacobsen, C. Kratky, K. Gruber, and N.E. Brasch (2007) Inorg Chem 46:3613-3618.
Homocysteine Transport by Human Aortic Endothelial Cells: Identification and Properties of Import Systems. B. Büdy, R.M. O’Neill, P.M. DiBello, S. Sengupta and D.W. Jacobsen (2006) Arch Biochem Biophys 446:119-130.
Molecular Targeting by Homocysteine: A Mechanism for Vascular Pathogenesis. D.W. Jacobsen, P.M.DiBello, C.O. Catanescu and J.C. Barbato (2005) Clin Chem Lab Med 43:107-83.
Modulation of Cystathionine b-Synthase Level Regulates Total Serum Homocysteine in Mice. L.Wang, K.-H. Jhee, X. Hua, P.M. DiBello, D.W. Jacobsen and W.D. Kruger (2004) Circ Res 94:1318-24.
In Vitro and in Vivo Interactions of Homocysteine with Human Plasma Transthyretin. A. Lim, S.Shantanu, M.E. McComb, R. Théberge, W.G. Wilson, C.E. Costello and D.W. Jacobsen (2003) J Biol Chem 278:49707-13.
Homocysteine Binds to Human Plasma Fibronectin and Inhibits Its Interaction with Fibrin. A.K. Majors, S. Sengupta, B. Willard, M. Kinter, R.E. Pyeritz and D.W. Jacobsen (2002) Arterioscler Thromb Vas Biol 22:1354-9.
Carmel, R., and D.W. Jacobsen (eds). (2001) Homocysteine in Health and Disease, Cambridge University Press, Cambridge, UK, 510 p.