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| Certification Type: |
Award, AHA Jeffrey M. Hoeg Award
Award, Franklin D. Murphy, M.D.
Award, Royal College of Physicians of Edinburgh
Award
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| Medical Degree: |
M.D., Johns Hopkins University School of Medicine, 1983
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| Degree: |
Ph.D., The Johns Hopkins University School of Medicine, 1983
B.S., University of Arizona, 1977
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| Medical Board Certification: |
Cardiovascular Disease, American Board of Internal Medicine, 1989
Internal Medicine, American Board of Internal Medicine, 1986
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Electrocardiographic Laboratory:
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(310)
825-7359
Information and referral
(310)
825-6301
ECG technician pager
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Physiology:
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310-206-5661
(Fax)
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| Mailing Address: |
David Geffen School of Medicine at UCLA
Medicine and Physiology
47-123 CHS
Los Angeles, CA 90095
UNITED STATES
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| Work Address: |
Office
CHS 17-052
UNITED STATES
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Work Phone Number:
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(310) 206-2677
Office
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Biomineralization in inflammatory diseases
Vascular calcification was previously considered an end-stage, inevitable process caused by passive crystal precipitation in dying cells. However, it is now known to be a common clinical occurrence closely linked to atherosclerosis. My research group demonstrated that calcium deposits in the artery wall are associated with expression of bone morphogenetic protein (BMP-2), a potent embryonic bone differentiation factor, and that fully-formed bone, cartilage and even marrow develop in atherosclerotic arteries in vivo. These findings suggest that the process is regulated at the molecular level and that it recapitulates embryonic programs.
To further study this process, we developed an in vitro model in which artery wall cells spontaneously undergo osteoblastic differentiation, tracking the same gene expression cascade characteristic of bone cells. We have isolated and cloned the cells that produce bone, cartilage and marrow tissue in the artery wall, and identified them as mesenchymal stem cells. We found that their differentiation is enhanced by exposure to oxidized lipids, such as isoprostanes, that are present in atherosclerotic lesions, as well as to inflammatory cytokines, thus accounting for the association of vascular calcification with atherosclerotic lesions and other chronic inflammatory processes. Our work took an interdisciplinary direction into bone biology, when we found that similar oxidized lipids are present in the walls of vessels in bone where they have the opposite effect, impairing bone mineralization and promoting resorption by osteoclastic cells, suggesting that lipid accumulation and inflammation in bone as well as vascular tissues may account for the occurrence of both vascular calcification and osteoporosis in the same patients.
Artery wall calcification has significant health implications given the increased risk of heart attack with calcified coronaries, the growing incidence of calcified aortic stenosis, use of mineralization-promoting agents in older women, and the widespread supplementation of foods with vitamin D.
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Biomineralization in inflammatory diseases
Vascular calcification was previously considered an end-stage, inevitable process caused by passive crystal precipitation in dying cells. However, it is now known to be a common clinical occurrence closely linked to atherosclerosis. My research group demonstrated that calcium deposits in the artery wall are associated with expression of bone morphogenetic protein (BMP-2), a potent embryonic bone differentiation factor, and that fully-formed bone, cartilage and even marrow develop in atherosclerotic arteries in vivo. These findings suggest that the process is regulated at the molecular level and that it recapitulates embryonic programs.
To further study this process, we developed an in vitro model in which artery wall cells spontaneously undergo osteoblastic differentiation, tracking the same gene expression cascade characteristic of bone cells. We have isolated and cloned the cells that produce bone, cartilage and marrow tissue in the artery wall, and identified them as mesenchymal stem cells. We found that their differentiation is enhanced by exposure to oxidized lipids, such as isoprostanes, that are present in atherosclerotic lesions, as well as to inflammatory cytokines, thus accounting for the association of vascular calcification with atherosclerotic lesions and other chronic inflammatory processes. Our work took an interdisciplinary direction into bone biology, when we found that similar oxidized lipids are present in the walls of vessels in bone where they have the opposite effect, impairing bone mineralization and promoting resorption by osteoclastic cells, suggesting that lipid accumulation and inflammation in bone as well as vascular tissues may account for the occurrence of both vascular calcification and osteoporosis in the same patients.
Artery wall calcification has significant health implications given the increased risk of heart attack with calcified coronaries, the growing incidence of calcified aortic stenosis, use of mineralization-promoting agents in older women, and the widespread supplementation of foods with vitamin D.
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Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, Stolina M, Kostenuik PJ, Demer LL Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr((-/-)) mice.
Circulation.
2008; 117(3):
411-420.
Yochelis A, Tintut Y, Demer LL, Garfinkel A The formation of labyrinths, spots and stripe patterns in a biochemical approach to cardiovascular calcification.
New Journal of Physics .
2008; 10:
.
Huang MS, Morony S, Lu JX, Zhang Z, Bezouglaia O, Tseng W, Tetradis S, Demer LL, Tintut Y Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and parathyroid hormone in osteoblasts.
Journal of Biological Chemistry.
2007; 282(29):
21237-21243.
Abedin M, Lim J, Tang TB, Park D, Demer LL, Tintut Y N-3 Fatty acids inhibit vascular calcification via the p38-MAPK and peroxisome proliferator-activated receptor-gamma pathways.
Circulation Research.
2006;
.
Demer LL, Tintut Y Pitting phosphate transport inhibitors against vascular calcification.
Circulation Research.
2006;
.
Tintut Y, Morony S, Demer LL Role of osteoprotegerin and its ligands and competing receptors in atherosclerotic calcification.
Journal of Investigative Medicine.
2006;
.
Radcliff, K Tang, TB Lim, J Zhang, Z Abedin, M Demer, LL Tintut, Y Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways.
Circulation research.
2005; 96(4):
398-400.
Tintut Y, Abedin M, Cho J, Choe A, Lim J, Demer L. Regulation of RANKL-induced osteoclastic differentiation by vascular cells.
J Molec Cell Cardiol.
2005; 39(2):
389-93.
Hsiai, TK Cho, SK Wong, PK Ing, MH Salazar, A Hama, S Navab, M Demer, LL Ho, CM Micro sensors: linking real-time oscillatory shear stress with vascular inflammatory responses.
Annals of biomedical engineering.
2004; 32(2):
189-201.
Demer LL, M Abedin Skeleton key to vascular disease.
J Amer Coll Cardiol.
2004; 44(10):
1977-9.
Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Bostrom K, Demer LL Multilineage potential of cells from the artery wall.
Circulation.
2003; 108:
2505-10.
Mody N, Demer LL Vascular calcification and its relation to bone calcification: Possible underlying mechanisms.
Journal of Nuclear Cardiology.
2003; 10:
177-83.
Tintut, Y Parhami, F Tsingotjidou, A Tetradis, S Territo, M Demer, LL 8-Isoprostaglandin E2 enhances receptor-activated NFkappa B ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway.
The Journal of biological chemistry.
2002; 277(16):
14221-6.
Demer, LL Adipose rex: Fat and fats that rule differentiation.
Circulation Research.
2002; 90:
241-243.
Hsiai T, Cho SK, Honda H, Hama S, Navab M, Demer L, Ho CM Endothelial cell dynamics under pulsating flows: Significance of high- vs. low shear stress slew rates (d(tau)/dt).
Annals of Biomedical Engineering.
2002; 30:
646-56.
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