Issued as final reportNASA AMES Research Ctr

Jo, Hanjoong

English

Scholarly Materials And Research @ Georgia Tech

Submission Date: 2/13/04 Final Progress Report Project Title: Molecular Basis of Mechano-Signal Transduction in Vascular Endothelial Cells PI Name: Hanjoong Jo PI Degree(s): Ph.D. PI Address: Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University 308 Woodruff Memorial Building 1639 Pierce Dr. Atlanta, GA 30322 PI PI PI Phone: Fax: Email: (404)712-9654 (404) 727-3330 hanjoong.jo@bme.gatech.edu Project Web Address: http://www.bme.gatech.edu/groups/jo/ Joint Agency: Co-Investigators / Affiliation: None NASA Facilities / Equipment used for this project: None Number of Funded Students: Pre-college: Undergraduate: Graduate: 2 (Nolan Boyd, Young-Mi Go) Post-doctoral: 2 (Heonyong Park, Yong Chool Boo) Monitoring Center: Grant Number: NASA NRA Solicitation: Total Funding: Start Date: End Date: ARC NAG 2-1348 98-HEDS-02 $772,822 08/01/1999 07/31/2003 S u m m a r y o f P r o g r e s s . 1 . W e found that caveo l in -1 regulates shear stress-dependent ac t i va t ion o f a member o f M A P kinase, E R K , i n bov ine aor t ic endothe l ia l cel ls ( B A E C ) . (see paper #1 ) . 2 . Ch ron i c p re - cond i t i on i ng o f B A E C w i t h laminar shear stress inh ib i t s express ion o f c a v e o l i n - 1 , decreases caveolae number , and improves subsequent shear response. (#8 ) . 3. Shear s t imulates a member o f M A P kinase, J N K , by the P I -3 -k inase and Ak t -dependen t mechan isms. ( # 2 , 3 ) 4 . Shear stress act ivates N O p roduc t i on b y regu la t ing phospho ry la t i on o f endothe l ia l N O synthase ( e N O S ) (#4 -8 , 10) 5. I den t i f i ca t i on o f B M P 4 as a mechanosensi t ive and i n f l a m m a t o r y c y t o k i n e lead ing to atherosclerosis deve lopment (#9 ) - (Patent f i l ed ) 6. I den t i f i ca t i on o f superox ide f r o m N A D P H oxidase as an i n f l a m m a t o r y mechan ism lead ing to atherosclerosis deve lopmen t (#11 ) P a p e r s P u b l i s h e d b y t h e N A S A f u n d i n g 1 . Park, H. , G o , Y - M , L i san t i M . P., M a l a n d M . C , J o , H . Caveo l i n regulates shear stress-dependent act ivat ion o f E R K , bu t no t J N K , i n endothel ia l cel ls. Am. J. Physiol. 2000 ; 2 7 8 : H 1 2 8 5 - H 1 2 9 3 . 2 . Go , Y . M . B o o , Y . C , Park, H . , M a l a n d , M . , Patel , R., D a r l e y - U s m a r , V . M . and J o , H . A k t / P r o t e i n K inase B Regulates F l o w - D e p e n d e n t A c t i v a t i o n o f cJun N - t e r m i n a l K i n a s e b y P r o d u c i n g N i t r i c O x i d e ( N O ) f r o m Endo the l i a l N O Synthase. J.ApplPhysiol 9 1 : 1 5 7 4 - 1 5 8 1 , 2 0 0 1 . 3. Go , Y . M . L e n o v e n A - L . , M o e l l e r i n g D., Patel RP. , J o , H . , and D a r l e y - U s m a r , V . M . Endo the l i a l n i t r i c o x i d e synthase-dependent ac t iva t ion o f J N K b y oxd i zed l o w densi ty l i pop ro te in . AmJ.PhysiolHeartCirc.Physiol 2$\:H2705-H2713, 2 0 0 1 . 4 . B o o , Y . C , G . Sorescu, N . B o y d , I . Sh io j ima , K . W a l s h , J. D u , and J o H . . Shear stress st imulates phosphory la t i on o f e N O S at S e r l l 7 9 b y A k t - independent mechan isms - R o l e o f P ro te in K inase A.JBiolChem 2 7 7 : 3 3 8 8 - 3 3 9 6 , 2 0 0 2 . 5. B o o , Y C , H w a n g J, Sykes M . , M i t c h e l l J . , K e m p B E , and J o H . Shear stress st imulates phosphory la t i on o f e N O S at S e r 6 3 5 residue by the p ro te in k inase A -dependen t mechan i sm. Am.J Physiol Heart Circ.Physiol. 2 8 3 : H 1 8 1 9 - H 1 8 3 7 , 2002 . 6. Bauer P M , F u l t o n D , B o o Y C , Sorescu GP, K e m p B E , J o H , Sessa W C . Compensa to ry phosphory la t i on and p ro te in -p ro te in interact ions revealed b y loss o f f u n c t i o n and ga in o f f unc t i on mutants o f m u l t i p l e serine phosphory la t i on sites in endothe l ia l n i t r i c o x i d e synthase. J Biol Chem. 278 :14841 -14849 , 2003 . 7. B o o , Y C and J o H . F l o w dependent regu la t ion o f endo the l ia l n i t r i c o x i d e synthase - R o l e o f p ro te in k inases. Am J Physiol Cell Physiol 285 : C 4 9 9 - C 5 0 8 , 2003 8. B o y d N , Park H , Y i H , B o o Y C , Sorescu GP, Sykes M , and J o H . Ch ron i c Shear Induces Caveolae Formai t ion and A l t e r s E R K and A k t Responses i n Endo the l i a l Ce l l s . Am. J Physiol Heart Circ.Physiol. 285 : H I 113 - 1122, 2003 . 9. Sorescu G P , Sykes M , We iss D , Piat t M O , Saha A , H w a n g J , B o y d N , B o o Y C , V e g a J D , T a y l o r W R , J o H . B o n e morphogen i c p ro te in 4 -produced in endo the l ia l cel ls b y osc i l l a to ry shear stress st imulates an i n f l a m m a t o r y response. J Biol Chem. 2 7 8 : 3 1 1 2 8 - 3 1 1 3 5 , 2 0 0 3 . 10 . B o o Y C , Sorescu G P , Bauer P M , Fu l t on D , K e m p B E , Ha r r i son D G , Sessa W C , a n d J o H . Phosphory la t i on o f e N O S at S e r 6 3 5 s t imulates N O p roduc t i on i n a Ca 2 + - i ndependen t manner . Free. Rod. Biol. Med. 2003 ;3 5: 7 2 9 - 4 1 . 1 1 . H w a n g J , Saha A , B o o Y C , Sorescu G P , M c N a l l y JS, H o l l a n d S M , D i k a l o v S, G iddens D P , G r i e n d l i n g K K , Ha r r i son D G , and J o H . Osc i l l a to ry shear stress st imulates endothe l ia l p roduc t i on o f 0 2 ~ f r o m p 4 7 p h o x - d e p e n d e n t N A D ( P ) H oxidases lead ing to m o n o c y t e adhesion. J Biol Chem. 2003;278 : 47291-8 A b s t r a c t s P u b l i s h e d aitid P r e s e n t e d 1. Park, H., Go, Y., Darji, R., Choi, J., Maland, M. C , and Jo, H. (1999). Caveolin-1 selectively mediates activation of ERK, but not JNK, by shear stress. FASEB J 13:752.3. 2. Go, Y.M., Maland, M., Patel, R., Park, H., Beckman, J.S., Darley-Usmar, V.M. and Jo, H. (1999). Evidence for peroxynitrite as a signaling molecule in flow-dependent activation of cJunN-terminal kinase. Free Rad Biol. Med. 1999; 27(Suppl. 1) S60. 3. Jo, H., Park, H., Maland, M., Patel, R., Darley-Usmar, V.M. and Go, Y.M. (1999). Shear stress stimulates JNK by activation of PI-3-kinase, AKT and endothelial NO synthase. Free Rad Biol. Med. 1999; 27(Suppl. 1) S62. 4. Moellering D.R., Go, Y.M., Maland, M., Patel, R., Park, H., Jo, H., and Darley-Usmar, V.M. (1999). A critical appraisal of hydrogen peroxide and superoxide as signaling molecules using the JNK/SAPK MAP kinase pathway. Free Rad Biol. Med. 1999; 27(Suppl. 1) S64. 5. Go, Y.M., Park, H., Maland, M., Patel, R., Darley-Usmar, V.M. and Jo, H. (1999). AKT/Protein kinase B regulates flow-dependent activation of cJun N-terminal kinase by producing NO from endothelial NO synthase. FASEB J. 14:A403, 303.10, 2000 6. Maland, M.,Park, H., Go, Y.M.and Jo, H. (1999). Ceramide regulates shear stress-dependent JNK activation in endothelial cells. FASEB J. 14:A449, 325.3, 2000 7. Park, H., Go, Y.M., Mitchell, L., Maland, M.and Jo, H. (1999). Fibronectin-dependent integrins regulate shear dependent activation of ERK. FASEB J. 14:A449, 325.5, 2000 8. Boyd N.L., Park H., and Jo H. (2001) Fluid Shear Stress Down-Regulates Caveolin-1 and Caveolin-2 Expression in Bovine Aortic Endothelial Cells. NASA Cell Sciences Conference 2001. 9. Boo Y., Jo, H. (2001) Shear stress phosphorylates eNOS by mechanisms dependentnt on protein kinase A, but not Akt. Oxygen Society meeting 10. Jo, H., Sykes, M., Sorescu, G., Hwang, J., Boyd, N. (2002) Effects of mechanical forces on gene expression profiles in mouse aortic endothelial cells. NASA Cell Sciences Conference 2001. 11. Hwang, J., Dupont K., Moon S., and Jo H. (2002) Laminar shear stress stimulates superoxide production by the p47phox-/- NADPH oxidase dependent mechanisms in mouse aortic endothelial cells. FASEB J 16:A379.10 12. Boo, Y. C , G. Sorescu, N. Boyd, I. Shiojima, K. Walsh, J. Du, and H. Jo. Shear stress stimulates phosphorylation of eNOS at Serl 179 by Akt- independent mechanisms - Role of Protein Kinase A. (2002) FASEB J 16:A643.24 13. Boo, Y. C , Hwang J, Sykes M., Griendling K., and H. Jo. Differential phosphorylation of eNOS at Ser 116, Thr497, Ser635 and Ser 1179 in response to mechanical and humoral stimuli in endothelial cells. (2002) FASEB J 16:A643.26 14. Hwang, J., Saha, A., Jo, H. Laminar shear (LSS) and oscillatory shear stress (OSS) differentially stimulate 0 2 - production and monocyte adhesion by NADPH dependent mechanisms in mouse aortic endothelial cells (MAEC). FASEB 2003 15. Boo, Y. C , Jo, H, Phosphorylation of eNOS at Ser635 stimulates NO production in a Ca 2 + -independent manner. FASEB 2003: 515.7 16. Sorescu, G., Sykes, M., Hwang, J., Saha, A., Jo, H. Bone morphogenic protein-4 (BMP4) induced by oscillatory shear (OS) mediates monocyte adhesion to endothelial cells (EC) - A novel role of BMP4 in inflammatory response and atherosclerosis. FASEB 2003: 864.1 17. Boyd, NB., Jo, H. Chronic shear exposure changes localization of caveolin-1 and caveolae in endothelial cells. FASEB 2003: 72.5. 18. A. Agahterhani, M. Whalin, Y.C. Boo, H. Jo and W.R. Taylor. Modulation of strain-mediated PAI-1 gene expression in vascular smooth muscle cells by cGMP-elevating agents: role of protein kinase A. FASEB 2003: 864.2 19. Lessner SM, Hwang J, Jo H, Galis ZS. Monocyte adhesion to aortic endothelial cells leads to contact-dependent increased MatrixMetalloproteinase-9 secretion. Circulation 2003 20. Magid R, Martinson D, Hwang J, Jo H, Zorina S Galis ZS. Isolation and in Vitro Functional Characterization of Primary Murine Aortic Endothelial Cell Cultures. Circulation 2003 21. Sorescu, G., Sykes, M., Hwang, J., Saha, A., Jo, H. Bone morphogenic protein-4 (BMP4) induced by oscillatory shear (OS) mediates monocyte adhesion to endothelial cells (EC) - A novel role of BMP4 in inflammatory response and atherosclerosis. Circulation 2003 New Direction Simulated microgravity studies using a random positioning machine (RPM). One RPM machine has been built for us by Fokker Science in Netherland. Using the device, we have developed an in vitro system to examine the effect of simulated microgravity on osteoblastic bone cells. Using this system, we have carried out gene chip studies to determine the gene expression profiles of osteoblasts cultured under simulated microgravity conditions in comparison to static controls. From this study, we have identified numerous genes, some of which are expected ones inducing bone loss, but many of which are unexpected and unknown. These findings are being prepared for publications. 

Molecular basis of mechano-signal transduction in vascular endothelial cells

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Molecular basis of mechano-signal transduction in vascular endothelial cells

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