Education:B.S. Biology, Mount St. Mary's College, Emmitsburg, MD
Ph.D. Biochemistry & Molecular Biology, The George Washington University, Washington, DC
Postdoctoral Fellow with Dr. Yusuf Hannun in the Biochemistry Department, MUSC, Charleston, SC
Research Interests:Targeting endothelial barrier dysfunction with HDL-S1P therapeutics
Thus far, attempts at therapeutic elevation of HDL have not proved useful in reducing cardiovascular disease (CVD) risk in humans, despite evidence from epidemiological studies indicating that high levels of HDL cholesterol (HDL-C) inversely associate with risk for CVD. Findings from the laboratory of Dr. Kelley Argraves indicate that compositional differences of sphingolipids carried by HDL are related to the occurrence of ischemic heart disease (IHD), and suggest that these differences may contribute to the putative protective role of HDL in IHD and other vascular disorders. Specifically researchers in the Argraves lab have found a highly significant inverse relationship between the level of sphingosine 1-phosphate (S1P) in the HDL-containing fraction of serum and the occurrence of IHD (1). These findings support the hypothesis that the atheroprotective activity of HDL is at least in part a function of S1P content, with higher levels being protective. This agrees with emerging evidence suggesting that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo. Research in the Argraves lab also highlights potential mechanisms by which HDL-S1P may mediate preservation of normal endothelial cell (EC) function as a key component of its atheroprotective effects. Brent Wilkerson, a graduate student in the Argraves lab, has demonstrated that the amount of S1P on HDL correlates with the magnitude of HDL-induced EC barrier. Alteration in EC barrier function is a critical factor underlying several CVD-related processes, including post ischemic edema, recruitment and migration of monocytes, and introduction of triglyceride-rich lipoprotein particles into the intima of blood vessels. Brent has also shown that HDL-S1P also significantly prolongs maintenance of EC barrier function as compared to the other major S1P carrier in blood, albumin. Furthermore, they have evidence that patients with increased endothelial permeability and edema resulting from cardiopulmonary bypass have a reduction in postoperative plasma levels of HDL, the principle carrier of S1P in blood (2). Moreover, they have found that relative to albumin-S1P, HDL-S1P significantly prolongs maintenance of the phosphorylated state of eNOS, which catalyzes production of nitric oxide, a modulator of vascular tone and EC barrier. Together, findings from the Argraves lab highlight the potential therapeutic utility of HDL-S1P or agents that augment HDL-S1P levels to combat EC barrier dysfunction and atherosclerosis.
Ongoing Research Support
NIH/NIGMS P20RR17677-01 Role: Core C Director 08/01/12 - 08/31/17
Title: COBRE in Lipidomics and Pathobiology
The overall goal of this COBRE is to develop and interactive Center of Lipidomics and Pathobiology to promote growth and excellence of research at MUSC. This involves three cores. Core C is the Animal Pathobiology Core.
NIH R21AG043718 Role: Co-PI 07/01/13 – 06/30/16
Role of Fibulin-1 in APP Processing
The major goal of this project is to 1) determine whether brain APP proteolytic cleavage is altered in Fbln1-defieint mice; 2) determine whether transgenic overexpression of Fbln1 accelerate Ab production and 3) determine whether Fbln1 inhibits a-sectrase processing of APP in cultured cells.
Completed Research Support (previous 3 years)
NSF EPSCoR RII GEAR Role: PI 10/01/14 – 03/31/16
Optimization of Endothelial Coverage and Endothelial Barrier on Biofabricated Blood Vessels
The major goal of this project is to optimize endothelial coverage and barrier function of biofabricated blood vessels with the long-term goal of using them in vivo.
NIH/NHBLI R21HL109829 Role: PI 04/01/12- 03/31/15
S1P Deficiency Prolongs Endothelial Barrier Recovery After Fontan Operation
The major goals of this project are 1) to determine whether plasma levels of S1P correlate with clinical markers of prolonged postoperative recovery after the Fontan operation, and 2) To determine the level of barrier integrity induced by plasma samples from patients and determine if there is correlation with S1P levels.
NIH/NIGMS P20RR7677-01 Pilot Project Program Role: PI of subaward 09/01/13 – 06/30/14
COBRE in Lipidomics and Pathobiology
Development of a novel live cell imaging approach to identify new S1P1 agonists that counteract loss of endothelial barrier function.
The major aim of this project is to define the internalization and trafficking patterns and kinetics of endothelial cell-S1PR1 in response to natural S1P.
NIH/NHBLI R21HL094883 Role: PI 07/01/09 - 07/31/12
HDL-Associated S1P as an Indicator of Relative Risk for Cardiovascular Disease
The major goals of this project are 1) Determine the prognostic value of HDL-S1P levels in assessing the risk for cardiovascular disease, 2) Determine if S1P levels in HDL inversely correlate with occurrence of IHD, 3) Determine if HDLs from subjects with low HDL-associated S1P are dysfunctional with respect to S1P.
- Guo C, Goodwin AJ, Buie JN, Cook JA, Halushka PV, Argraves K, Zingarelli B, Zhang XK, Wang L, Fan H. A Stromal Cell-derived Factor 1 alpha Analogue Improves Endothelial Cell Function in Lipopolysaccharide-induced Acute Respiratory Distress Syndrome. Mol Med. 2016, Mar 18 PMID: 27031787
- Yu H, Herbert BA, Valerio M, Yarborough L, Hsu LC, Argraves KM. (2015) FTY720 inhibited proinflammatory cytokine release and osteoclastogenesis induced by Aggregatibacter actinomycetemcomitans. Lipids Health Dis. 2015 Jul 4;14:66. doi: 10.1186/s12944-015-0057-7. PMID: 26138336
- Yu H, Sun C, Argraves KM. (2015) Periodontal inflammation and alveolar bone loss induced by Aggregatibacter actinomycetemcomitans is attenuated in sphingosine kinase 1-deficient mice. J Periodontal Res. 2015 Apr 20. doi: 10.1111/jre.12276. [Epub ahead of print] PMID: 25900155
- Harikrishnan K, Cooley MA, Sugi Y, Barth JL, Rasmussen LM, Kern CB, Argraves KM, Argraves WS. (2015) Fibulin-1 suppresses endothelial to mesenchymal transition in the proximal outflow tract. Mech Dev. 2015 Jan 6. pii: S0925-4773(14)00091-4. doi: 10.1016/j.mod.2014.12.005. Epub ahead of print. PMID: 25575930
- Wilkerson BA, Argraves K.M. (2014) The role of sphingosine-1-phosphate in endothelial barrier function. Biochim Biophys Acta. 2014 Oct;1841(10):1403-1412. doi: 10.1016/j.bbalip.2014.06.012. Epub 2014 Jul 5. PMID: 25009123
- Aseem O, Smith BT, Cooley MA, Wilkerson BA, Argraves K.M., Remaley AT, Argraves WS. (2014) Cubilin Maintains Blood Levels of HDL and Albumin. J Am Soc Nephrol. 2014 May;25(5):1028-36. doi: 10.1681/ASN.2013060671. Epub 2013 Dec 19. PMID: 24357674
- Wilkerson BA, Grass GD, Wing SB, Argraves WS, Argraves K.M. (2012) S1P Carrier-Dependent Regulation of Endothelial Barrier: HDL-S1P Prolongs Endothelial Barrier Enhancement as Compared to Albumin-S1P Via Effects on Levels, Trafficking and Signaling of S1P1. J Biol Chem. 2012 Dec 28;287(53):44645-53. PMID:23135269
- Zyblewski SC, Argraves WS, Graham EM, Slate EH, Atz AM, Bradley SM, McQuinn TC. Wilkerson BA, Wing SB, Argraves K.M. (2012) Reduction in post-operative HDL cholesterol levels in children undergoing the Fontan operation. Pediatr Cardiol. 2012 Oct;33(7):1154-9. PMID:22411716
- Bohonowych J.E., Peng S., Gopal U, Hance MW, Wing SB, Argraves K.M., Lundgren K., Isaacs JS. (2011) Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation. BMC Cancer. 2011 Dec 15;11(1):520. PMID:22172030
- Argraves K.M.*, Sethi AA, Gazzolo PJ, Wilkerson BA, Remaley AT, Tybjaerg-Hansen A, Nordestgaard BG, Yeatts SD, Nicholas KS, Barth JL, Argraves WS. (2011) S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease. Lipids Health Dis. 2011 May 9;10(1):70. PMID: 2155469
- Argraves, K.M., Wilkerson, B.A. and Argraves, W.S. (2010) Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis. World J Biol Chem 2010 Oct 26;1(10):291-7. doi: 10.4331/wjbc.v1.i10.291. PMID: 21537462
- Argraves WS, Tanaka A, Smith EP, Twal WO, Argraves KM, Fan D, Haudenschild CC. (2009) Fibulin-1 and fibrinogen in human atherosclerotic lesions. Histochem Cell Biol. Nov;132(5):559-65. doi: 10.1007/s00418-009-0628-7. Epub 2009 Aug 20. PMID: 19693531.
- Gentile C., Fleming P.A., Mironov V., Argraves K.M., Argraves W.S., Drake C.J.(2008)VEGF-mediated fusion in the generation of uniluminal vascular spheroids.Dev Dyn. 237(10):2918-25.
- Argraves, K.M., Gazzolo, P.J., Groh, E.M., Wilkerson, B.A., Matsuura, B.S., Twal, W.O., Hammad, S.M., and Argraves, W.S. (2008) High density lipoprotein-Associated Sphingosine-1-Phosphate Promotes Endothelial Barrier Function. J Biol Chem. Sep 5; 283(36):25074-81. PMID: 18606817
- Argraves, K.M. and Argraves, W.S. (2007) HDL serves as an S1P signaling platform mediating a multitude of cardiovascular effects. J. Lipid Res. 48(11):2325-2333.
- Argraves, K.M., Wilkerson, B.A., Argraves, W.S., Fleming, P.A., Obeid, L.M., and Drake, C.J. (2004) Sphingosine-1-Phosphate Signaling Promotes Critical Migratory Events in Vasculogenesis. J. Biol. Chem. 279: 50580-90.
- Taha, T.A., Argraves, K.M., and Obeid, L.M. (2004) Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. BBA 1;1682(1-3):48-55.
- Argraves, K.M., Obeid, L.M., and Hannun, Y.A. (2002) Sphingolipids in vascular biology. Proceedings for: Eicosaniods and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury. Edited by Honn et al., Kluwer Acdemic/Plenum Publishers, 439-444.
- Mikhailenko, I., Battey, F.D., Migliorini, M., Ruiz, J.F., Argraves, K., Moayeri, M., and Strickland, D.K. (2001) Recognition of a2-macroglobulin by the LDL receptor-related protein (LRP) requires the cooperation of two ligand binding cluster regions. J. Biol. Chem. 276:39484-39491.
- Hannun, Y.A., Luberto, C., and Argraves, K.M. (2001) Enzymes of Sphingolipid Metabolism: From Modular to Integrative Signaling. Biochemistry 40:4893-4903.
- Mikhailenko, I., Considine, W., Argraves, K.M., Loukinov, D., Hyman, B.T., Strickland, D.K. (1999) Functional domains of the very low density lipoprotein receptor: molecular analysis of ligand binding and acid-dependent ligand dissociation mechanisms. J Cell Sci 112:3269-81.
- Barth, J. L., Argraves, K.M., Roark, E. F., Little, C. D. and Argraves, W.S. (1998) Identification of chicken and C. elegans fibulin-1 homologs and characterization of the C. elegans fibulin-1 gene. Matrix Biol. 17(8-9):635-46.
- Argraves, K.M., Kozarsky, K.F., Fallon, J.T., Harpel, P.C., and Strickland, D.K. (1996) The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. J Clin Invest 1997 100:2170-81.
- Mikhailenko, I., Krylov, D., Argraves, K.M., Roberts, D.D., Liau, G., and Strickland, D.K. (1996) Cellular internalization and degradation of thrombospondin-1 is mediated by amino-terminal heparin-binding domain (HBD): High affinity interaction of HBD with the low density lipoprotein receptor-related protein (LRP). J. Biol. Chem. 272: 6784-6791.
- Argraves, K.M., Battey, F.D, MacCalman, C.D., McCrae, K.R., Chappell, D.A., Strauss, J.F. III, and Strickland, D. K. (1995) The very low density lipoprotein receptor mediates cellular catabolism of lipoprotein lipase and urokinase-plasminogen activator inhibitor type I complexes. J. Biol. Chem. 270: 26550-26557.
- Stefansson, S., Chappell, D.A., Argraves, K.M., Strickland, D.K., and W.S. Argraves (1995) Glycoprotein 330/low density lipoprotein receptor-related protein-2 endocytosis of low density lipoproteins via interaction with apolipoprotein B100. J. Biol. Chem. 270:19417-19421.
- Williams, S. E., Kounnas, M. Z., Argraves, K.M., Argraves, W. S., and Strickland, D. K. (1994) The a2-macroglobulin receptor/low density lipoprotein receptor-related protein and the receptor associated protein: an overview. Ann. N. Y. Acad. Sci. 737:1-13.
- Kounnas, M.Z., Stefansson, S., Loukinova, E., Argraves, K.M., Strickland, D.K. And Argraves, W.S. (1994) An overview of the structure and function of glycoprotein 330, a receptor related to the a2-macroglobulin receptor. Ann. N. Y. Acad. Sci. 737:114-123.
- Korenberg, J.R., Argraves, K.M., Chen, X-N., Tran, H., Strickland, D. K. and Argraves, W.S. (1994) Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 and its associated protein RAP. Genomics 22:88-93.
- Guan, E., Burgess, W.H., Robinson, S.L., Goodman, E.B., McTigue, K.J. and Tenner, A.J. (1992) Phagocytic cell molecules that bind the collagen-like region of C1q. J. Biol. Chem. 266: 20345-20355.
- Strickland, D.K., Ashcom, J.D., Williams, S., Battey, F., Behre, E., McTigue, K., Battey, J.F., and Argraves, W.S. (1992) Primary structure of a2-macroglobulin receptor associated protein: human homologue of a Heymann nephritis antigen. J. Biol. Chem. 266: 13364-13369.