Aviv I. Hassid, Ph.D.

Aviv I. Hassid, Ph.D.

Professor of Physiology
Phone: 901-448-8304
Fax: 901-448-7126
Full CV


1966 B.S. Robert College, Istanbul, Turkey
1974 Ph.D., University of Minnesota Minneapolis, Minnesota

Research Interest

Project 1: Nitric Oxide-PTP Interactions In Aortic Smooth Muscle

This is a proposal to investigate the role of protein tyrosine phosphatase PTPIB as mediator of the inhibitory effects of nitric oxide (NO) in vascular smooth muscle and in vascular remodeling. NO plays a major inhibitory role in neointima formation after vascular injury. Mechanisms explaining this effect in cultured cells and especially in vivo are lacking. We have found that NO increases the activity of PTPIB in cultured rat aortic smooth muscle cells, without increasing its protein levels. Moreover, we have found that PDGF and FGF increase PTP1B protein levels in cultured cells and that vascular injury similarly induces increased PTP1B protein levels in injured rat carotid artery. We have also shown that NO targets the IGF1 receptor, inducing receptor tyrosine dephosphorylation and interrupting IGFl-induced signal transduction in cultured cells. Finally, we have shown that NO decreases cytoplasmic Ca and attenuates IGFl-induced hydrogen peroxide generation and that this effect is mimicked by independent lowering of intracellular Ca by a Ca chelator. These results support a possible involvement of reduced Ca in activating PTP1B. The role of IGF1 in vascular injury is currently unclear. On the one hand, vascular injury induces upregulation of IGF1 levels but on the other, IGF1 receptor mRNA levels and IGF1 receptor binding are decreased. Consistent with these findings, we have found that vascular injury decreases IGF1 receptor protein levels by about 30%, as determined by Western blot analysis; moreover, we have found that receptor activation, as measured by specific receptor tyrosine phosphorylation, is decreased by more than 80%. These novel and exciting findings describe for the first time a mechanistic link between NO and tyrosine kinase receptor dephosphorylation involving a protein tyrosine phosphatase. Taken together, our results raise the possibility
of negative cross-talk between, on the one hand PDGF or FGF, and on the other IGF1 signal transduction, via the intermediacy of elevated PTP1B. Based on the above, we propose the following specific aims, to be performed in cultured rat aortic smooth muscle cells or in rats or mice: Determine whether reduction of cytoplasmic Ca is necessary and/or sufficient to induce upregulation of PTP1B activity. Determine whether
upregulation of PTP1B is necessary and/or sufficient to account for NO-induced inhibition of cell proliferation and induction of apoptosis in cultured cells. Determine whether PDGF, FGF or NO induce upregulation of PTP1B protein or activity levels in vascular injury. Determine whether PTPIB plays a role in NO-induced decrease of cell proliferation, motility, apoptosis and neointima formation in models of rat or mouse vascular injury. Determine whether PTP1B plays a role in attenuating IGF receptor activation in vivo.

Project 2: NO-induced vascular smooth muscle cell motility

Nitric oxide (NO) is generally considered to play a protective role in blood vessels. However, others and we have obtained evidence that this may not always be the case but the mechanisms underlying diverse responses to NO are not known. The purpose of this proposal is to test an exciting new hypothesis on the capacity of chronically elevated insulin levels to switch the role of nitric oxide from protective to deleterious substance in blood vessels. We have found that the inhibitory effects of NO on both motility and proliferation are abrogated in vascular smooth muscle cells chronically treated with insulin. These findings support a new hypothesis on the role of insulin as a switcher of vascular smooth muscle cell phenotypic responses to NO. Our preliminary results indicate that the motility-stimulatory effect of NO, uncovered by chronic insulin
treatment of cultured rat aortic smooth muscle cells, is associated with increased PI 3 kinase activity and requires the functional availability of angiotensin II, of the adapter protein Gab1 and the protein tyrosine phosphatase SHP2. Studies by others have found that Gab1 can be recruited to the plasma membrane via increased PIPS levels. However, the mechanistic linkage of chronic insulin treatment to Gab1 and SHP2 function has not been defined. Moreover, experiments to determine whether similar mechanisms may be
applicable to abrogation of the antiproliferative effect of NO by chronic insulin treatment have not been performed. Finally, the pathophysiological significance of our results is unknown. We propose to implement the following specific aims: Aim 1. To determine whether increased angiotensin II function is necessary and/or sufficient to account for the effect of insulin on PI3K activity and NO-induced cell motility. Aim 2. To determine whether chronic insulin treatment recruits Gab1 to the cell membrane and whether insulin independent recruitment of Gab1 or SHP2 to the cell membrane can mimic the motility-stimulatory effect of NO uncovered by chronic insulin treatment. Aim 3: To uncover mechanisms that describe how hyperinsulinemia attenuates the effect of NO as inhibitor of PDGF-induced DNA synthesis, in cultured rat aortic smooth muscle cells. Aim 4. To determine whether expression of inducible nitric oxide synthase in vascular injury enhances neointima formation in hyperinsulinemic mice, but has the opposite effect in
normoinsulinemic mice or in hyperinsulinemic mice treated with an AT1 receptor antagonist.

Research Support

R01 HL63886;    Hassid (PI)                    1/1/06-12/31/09
Role: PI    
NO-stimulated cell motility: This project targets the role of role of hyperinsulinemia as a determinant of the effect of nitric oxide in vascular injury, both in vitro and in vivo.   

R01 HL72902;    Hassid (PI)                    7/1/04-6/30/08
Role: PI
Nitric oxide-PTP interactions in aortic smooth muscle: This project targets the role of PTP1B in NO-induced inhibition of aortic smooth muscle cell motility. 

Maury W. Bronstein Endowed Chair; Hassid (PI)        7/1/91-indefinite
University of Tennessee
Role: PI
This is an unrestricted fund with no specific aims, used to obtain the current preliminary data.

Selected Publications

Publications: 2003-Present 

  1. Bhanoori, M., C. R. Yellaturu, S. K. Ghosh, A. Hassid, L. K. Jennings, and G. N. Rao. Thiol alkylation inhibits the mitogenic effects of platelet-derived growth factor and renders it proapoptotic via activation of STATs and p53 and induction of expression of caspase1 and p21(waf1/cip1). Oncogene 22(1):117-130. (2003).
  2. Yigzaw, Y., H. M. Poppleton, N. Sreejayan, A. Hassid, and T. B. Patel. Protein-tyrosine Phosphatase-1B (PTP1B) Mediates the Anti-migratory Actions of Sprouty. J Biol Chem 278(1):284-288. (2003).
  3. Lin, Y., Ceacareanu, A. C., and Hassid, A. Nitric oxide-induced inhibition of aortic smooth muscle cell motility: role of PTP-PEST and adaptor proteins p130cas and Crk. Am J Physiol Heart Circ Physiol 285(2), H710-721 (2003)
  4. Dixit, M., D. Zhuang, B. Ceacareanu, and A. Hassid. Treatment with insulin uncovers the motogenic capacity of nitric oxide in aortic smooth muscle cells: dependence on Gab1 and Gab1-SHP2 association. Circ Res 93(10):e113-123 (2003).
  5. Zhuang, D., Ceacareanu, A-C., Lin Yi, Ceacareanu, B., Dixit, M., Chapman, K.E., Waters, C.M., Rao, G.N., and Hassid, A. Nitric oxide attenuates insulin- or IGF1-stimulated aortic smooth muscle cell motility by decreasing hydrogen peroxide levels. Essential role of Cyclic GMP. Am J Physiol Heart Circ Physiol 286:H2103-211276 (2004).
  6. Chang Y, Zhuang D, Zhang C, Hassid A. Increase of PTP levels in vascular injury and in cultured aortic smooth muscle cells treated with specific growth factors. Am J Physiol Heart Circ Physiol. 2004;287:H2201-2208.
  7. Tomar A, Wang Y, Kumar N, George S, Ceacareanu B, Hassid A, Chapman KE, Aryal AM, Waters CM, Khurana S. Regulation of cell motility by tyrosine phosphorylated villin. Mol Biol Cell. 2004;15:4807-4817.
  8. Desai LP, Aryal AM, Ceacareanu B, Hassid A, Waters CM. RhoA and Rac1 are both required for efficient wound closure of airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2004;287:L1134-1144.
  9. Zhuang D, Ceacareanu AC, Ceacareanu B, Hassid A. Essential role of protein kinase G and decreased cytoplasmic Ca2+ levels in NO-induced inhibition of rat aortic smooth muscle cell motility. Am J Physiol Heart Circ Physiol. 2005;288:H1859-1866. Epub 2004 Dec 1852.
  10. Chang Y, Ceacareanu B, Zhuang D, Zhang C, Pu Q, Ceacareanu AC, Hassid A. Counter-regulatory function of protein tyrosine phosphatase 1B in platelet-derived growth factor- or fibroblast growth factor-induced motility and proliferation of cultured smooth muscle cells and in neointima formation.Arterioscler Thromb Vasc Biol. 2006;26:501-507.
  11. Ceacareanu AC, Ceacareanu B, Zhuang D, Chang Y, Ray RM, Desai L, Chapman KE, Waters CM, Hassid A. Nitric oxide attenuates IGF-I-induced aortic smooth muscle cell motility by decreasing Rac1 activity: essential role of PTP-PEST and p130cas. Am J Physiol Cell Physiol.2006;290:C1263-1270. Epub 2005 Dec 1214.
  12. Dixit M, Loot AE, Mohamed A, Fisslthaler B, Boulanger CM, Ceacareanu B, Hassid A, Busse R, Fleming I. Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial NO synthase by fluid shear stress. Circ Res. 2005;97:1236-1244. Epub 2005 Nov 1210.
  13. Chapman KE, Sinclair SE, Zhuang D, Hassid A, Desai LP, Waters CM. Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2005;289:L834-841. Epub 2005 Jun 2017.
  14. Liu X, Sun SQ, Hassid AI, Ostrom RS. cAMP inhibits TGFbeta-stimulated collagen synthesis via inhibition of erk1/2 and smad signaling in rat cardiac fibroblasts. Mol Pharmacol. 2006; 70:1992-2003. Epub 2006 Sep 7.
  15. Rafiq K, Kolpakov MA, Abdelfettah M, Streblow DN, Hassid A, Dell'Italia LJ, Sabri A. Role of protein-tyrosine phosphatase SHP2 in focal adhesion kinase down-regulation during neutrophil cathepsin G-induced cardiomyocytes anoikis. J Biol Chem. 2006;281:19781-19792. Epub 12006 May 19711.
  16.  Desai LP, Sinclair SE, Chapman KE, Hassid A, and Waters CM. High tidal volume mechanical ventilation with hyperoxia alters alveolar type II cell adhesion. Am J Physiol Lung Cell Mol Physiol 293: L769-778. Epub 2007 Jun 2029., 2007.