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More about
Dr. Lupu:

Dr. Lupu's CV in brief

Publications

Cardiovascular Biology Research Program

Florea Lupu, Ph.D. Associate Member / Sr. Lab Director, Cardiovascular Biology Research   Program Adjunct Assistant Professor, Department of Pathology, University of Oklahoma   Health Sciences Center

Research Interests
Our research focuses on the investigation of the cell surface mechanisms of tissue factor-factor VIIa (TF-FVIIa) inhibition by tissue factor pathway inhibitor (TFPI). TF is a transmembrane protein that triggers blood coagulation in vivo. Among other effects, TF elicits thrombogenic responses in septicemia, cancer and atherosclerosis. Formation of the TF-FVIIa-FXa-TFPI complex provides sustained repression of the TF pathway. In vivo, most TFPI associates with caveolae in EC. The mechanism of this association and the anticoagulant role of caveolar TFPI are not yet known. By using HEK 293, a cell system where we controlled the expression of both TFPI and caveolin-1 by transfection, we observed that caveolin/caveolae keep TFPI exposed on the plasmalemma surface, decrease the membrane lateral mobility of TFPI and increase the TFPI-dependent inhibition of TF-FVIIa. Caveolae-associated TFPI supports the co-localization of the quaternary complex with caveolae. Further, we used RNA interference technology to deplete EC of caveolin-1 and thus to test the possible physiological significance of these observations for EC. Functional assays and fluorescence microscopy revealed that the inhibitory properties of TFPI diminished in EC lacking caveolin-1, apparently through deficient assembly of the quaternary complex. Our studies identified caveolin-1 as an active regulator of TFPI-dependent inhibition of TF-FVIIa activity, therefore adding the haemostatic dimension as a novel dimension to the biological significance of caveolae.

On a parallel line of investigation, we study the alteration of EC hemostatic properties in severe sepsis in relationship to the expression and function of TF and TFPI. The hallmark of sepsis is represented by EC dysfunction, characterized as an excessive, sustained and generalized activation of the endothelium. Accordingly, we investigated whether localized changes of endothelial function in areas of the arterial tree exposed to perturbed flow may contribute to the severe sepsis phenotype. To verify our hypothesis, we compared the expression and function of various pro- and antithrombotic proteins in straight versus branched segments of arteries in healthy and septic baboons. Confocal microscopy and 3D rendering were used to obtain en-face images of whole-mount arterial segments after immunostaining with fluorescent markers for coagulation-specific proteins. We observed that the endothelial responses to E. coli differ according to the spatial geometry of the arteries, showing increased TF- dependent coagulant function at branches, when compared to the straight segments of arteries. These data suggest that site-dependent endothelial heterogeneity and rheological factors possibly contribute to a focally enhanced procoagulant response to E. coli.

In the long term, our studies should facilitate the understanding of the patho-physiology of blood clotting associated with sepsis and may provide clues for the development of new therapeutic approaches.

Joined OMRF Scientific Staff in 2001.

Mailing Address
Cardiovascular Biology Research Program, MS 45
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104

Contact Information
Phone: (405) 271-7468
Fax: (405) 271-7417
E-mail: Florea-Lupu@omrf.org