Vasospasm occurs unexpectedly and unpredictably during peripheral and aortocoronary bypass graft reconstructions. We propose that some forms of vasospasm are due to impaired cyclic nucleotide-dependent vasorelaxation of the vascular smooth muscle. Using a model of vasospasm, human umbilical artery smooth muscle (HUASM), we have determined that a major phosphoprotein substrate during cyclic nucleotide-dependent vasorelaxation is a small heat shock protein, HSP2O. Other investigators have implicated, another small HSP, HSP27, in contraction of smooth muscles and have found that HSP27 expression is increased, specifically in the vasculature, by stress. The hypothesis of this investigation is that the phosphorylation of HSP2O modulates cyclic nucleotide-dependent vasorelaxation and that alterations in the expression or phosphorylation of HSP27 lead to the inhibition of HSP2O phosphorylation and vasospasm.
The specific aims are to: 1) Determine the signal transduction events that lead to the phosphorylation of small HSPs during contraction and relaxation of vascular smooth muscles; and 2) Determine the specific functions of small HSPs in vascular smooth muscle contraction and relaxation. Physiologic responses will be determined in a muscle bath and correlated with signal transduction events. Responses in normal vascular smooth muscle (bovine carotid artery smooth muscle) will be compared to the muscle that is a model of vasospasm (human and bovine umbilical artery smooth muscle). Using these systems we plan to determine the specific role of heat shock proteins in vasospasm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058027-03
Application #
2901295
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1997-04-05
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Dreiza, Catherine M; Komalavilas, Padmini; Furnish, Elizabeth J et al. (2010) The small heat shock protein, HSPB6, in muscle function and disease. Cell Stress Chaperones 15:1-11
Lopes, Luciana B; Flynn, Charles; Komalavilas, Padmini et al. (2009) Inhibition of HSP27 phosphorylation by a cell-permeant MAPKAP Kinase 2 inhibitor. Biochem Biophys Res Commun 382:535-9
Lopes, Luciana B; Furnish, Elizabeth J; Komalavilas, Padmini et al. (2009) Cell permeant peptide analogues of the small heat shock protein, HSP20, reduce TGF-beta1-induced CTGF expression in keloid fibroblasts. J Invest Dermatol 129:590-8
Komalavilas, Padmini; Penn, Raymond B; Flynn, Charles R et al. (2008) The small heat shock-related protein, HSP20, is a cAMP-dependent protein kinase substrate that is involved in airway smooth muscle relaxation. Am J Physiol Lung Cell Mol Physiol 294:L69-78
Flynn, Charles R; Smoke, Christopher C; Furnish, Elizabeth et al. (2007) Phosphorylation and activation of a transducible recombinant form of human HSP20 in Escherichia coli. Protein Expr Purif 52:50-8
Lopes, Luciana B; Brophy, Colleen M; Furnish, Elizabeth et al. (2005) Comparative study of the skin penetration of protein transduction domains and a conjugated peptide. Pharm Res 22:750-7
Dreiza, Catherine M; Brophy, Colleen M; Komalavilas, Padmini et al. (2005) Transducible heat shock protein 20 (HSP20) phosphopeptide alters cytoskeletal dynamics. FASEB J 19:261-3
Tessier, Deron J; Komalavilas, Padmini; McLemore, Elisabeth et al. (2004) Sildenafil-induced vasorelaxation is associated with increases in the phosphorylation of the heat shock-related protein 20 (HSP20). J Surg Res 118:21-5
Huey, Kimberly A; Thresher, Jeffrey S; Brophy, Colleen M et al. (2004) Inactivity-induced modulation of Hsp20 and Hsp25 content in rat hindlimb muscles. Muscle Nerve 30:95-101
Tessier, Deron J; Komalavilas, Padmini; Liu, Bo et al. (2004) Transduction of peptide analogs of the small heat shock-related protein HSP20 inhibits intimal hyperplasia. J Vasc Surg 40:106-14

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