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C. Keith Ozaki
M.D., FACS |
OBJECTIVES: The overall aim of Dr. Ozaki's research mechanisms in the adaptations (neointimal hyperplasia, arteriogenesis) of blood vessels (both arteries and vein grafts) to various hemodynamic forces.
RESEARCH APPROACHES: The experimental approach relies heavily
on in vivo models, combined with biochemical, cell culture, immunologic and molecular techniques.
RECENT FINDINGS: Studies to date in arteries have determined that low shear stress in arteries induces TNF-α and IL-1b mRNA, and lack of these cytokines through genetic deletion attenuates neointimal hyperplasia in this setting. Surprising, IL-10 signaling does not appear to mediate or modulate this process. Paradoxically, certain cytokines such as TNF-a are also up-regulated in positive arterial remodeling and high shear stress (e.g. arteriogenesis), and abrogation of TNF-a in this setting attenuates the positive arterial remodeling. Hemodynamically driven changes in pro- and anti-inflammatory cytokine activities also appear to occur in vein grafts, and recent work suggests that manipulation of these mediators may stand as an effective approach to block pathologic vein graft adaptations.
CLINICAL RELEVANCE: The results of this work will better elucidate the roles of inflammatory mediators and signaling mechanisms in vascular biology. This will positively impact the care of the patient with vascular disease, such as those who require bypass grafts.
PUBLICATIONS:
1.
Rectenwald JE, Moldawer LL, Huber TS, Seeger JM, Derrow AE, Warren
JA, Ozaki CK. Direct evidence for cytokine involvement in
neointimal hyperplasia. Circulation, 2000;102:1697-1702.
2.
Rectenwald JE, Pretus HA, Seeger JM, Huber TS,
Mendenhall NP, Zlotecki RA, Palta JR, Li ZF, Hook SY, Sarac TP,
Welborn MB, Klingman NV, Abouhamze ZS, Ozaki CK. Radiation
therapy for improved dialysis access patency: feasibility and early
safety. Radiation Research. 2001;156:53-60.
3.
Rectenwald JE, Minter RM, Moldawer LL, Abouhamze Z,
La Face D, Hutchins E, Huber TS, Seeger JM, Ozaki CK.
Interleukin-10 fails to modulate low shear stress induced neointimal
hyperplasia. J Surg Res, 2002;102(2):110-118.
4.
Hoefer IE, van Royen N, Rectenwald JE, Bray EJ,
Abouhamze Z, Moldawer LL, Vokuil M, Piek JJ, Buschmann IR, Ozaki
CK. Direct evidence for TNF-a
signaling in arteriogenesis. Circulation,
2002;105:1639-1641.
5.
Jiang Z, Wu L, Miller BL, Goldman DR, Fernandez CM,
Abouhamze ZS, Ozaki CK, Berceli SA. A novel vein graft
model: adaptation to differential flow environments. Am J
Physiol Heart Circ Physiol. 2004; 286(1):H240-5.
6.
Berceli SA, Jiang Z, Klingman N, Pfahnl CL, Abouhamze
ZS, Frase C, Schultz GS, Ozaki CK. Differential expression
and activity of MMPs during flow-modulated vein graft remodeling.
J Vasc Surg 2004;39:1084-1090.
7.
Hoefer IE, van Royen N, Rectenwald JE, Deindl
E, Hua J, Jost M, Heil M, Grundmann MV,
Ozaki CK,
Piek JJ, Buschman IR.
Arteriogenesis
proceeds via ICAM-1/Mac-1 mediated mechanisms. Circ. Res
2004;94:1179-1185.
8.
Jiang Z, Berceli SA, Pfahnl CL, Wu L, Goldman DR, Tao
M, Kagayama M,
Matsukawa
A, Ozaki CK. Wall shear modulation of cytokines in the early
vein graft. J Vasc Surg 2004;40:345-350.
9.
Jiang Z, Berceli SA, Pfahnl CL, Wu L, Killingsworth CD, Vieira FG,
Ozaki CK. Impact of IL-1b
on flow induced outward arterial remodeling. Surgery
2004;136:478-482.
10.
Perrault-Dematte CM, Bray EJ, Didier N, Ozaki CK,
Tran-Son-Tay R. Altered rheology of lymphocytes in diabetic mice.
Diabetologia
2004;47(10):1722-1726.
11.
Fernandez CM, Goldman DR, Jiang Z, Ozaki CK, Tran-Son-Tay R,
Berceli SA. Impact of shear stress on early vein graft remodeling:
a biomechanical analysis. Ann Biomed Eng
2004;32(11):1484-1493.
12.
Grundmann S, Hoefer I, Ulusans S, van Royen N,
Schirmer S, Ozaki CK, Bode C, Piek JJ, Buschmann I.
Anti-Tumor necrosis factor-a
therapies attenuate adaptive arteriogenesis in rabbits. Am J
Physiol Heart Circ Physiol. 2005 May 27 [Epub ahead of print].
13.
Jiang Z, Berceli SA, Pfahnl CL, Wu L, Miller BL,
Ozaki CK. Differential temporal expression and wall shear
stress modulation of
TNF-a
and IL-10 expression-impact on remodeling. Submitted.
14.
Berceli SA, Jiang Z, Kilingman NV, Schultz GS,
Ozaki CK. Flow regulation of MMP-2 and -9 during arterial and
vein graft adaptations. Submitted.
15.
Zacharski LR, Chow BK, Howes PS, Lavori PW, Shamayeva
G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK. Reduction of
iron stores by phlebotomy in peripheral vascular disease: protocol
compliance and toxicity. VA Cooperative Study #410: The Iron (Fe)
and Atherosclerosis Study (FeAST). Submitted.
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