Abstract

Vasospasm contributes to vein graft spasm during vascular reconstructive surgery, non-occlusive mesenteric ischemia' Raynaud's syndrome, and cerebral ischemia after subarachnoid hemorrhage. Our understanding of the pathophysiology of vasospasm is limited, largely due to a lack of good models. However, a fundamental principal of vasospasm is that the vascular smooth muscle is refractory to relaxation. We have determined that cyclic nucleotide-dependent relaxation is associated with increases in the phosphorylation of the small heat shock-related protein, HSP20. We have developed a physiologic model of vasospasm, umbilical artery smooth muscle, which is uniquely refractory to relaxation and in this muscle, HSP20 is not phosphorylated. Another, closely related heat shock protein, HSP27,is highly expressed in muscle and is induced by stress. Elevated levels of phosphorylated HSP27 are associated with impaired relaxation and phosphorylation of HSP20, suggesting that phosphorylated HSP27 modulates contractile function by inhibiting the phosphorylation of HSP20. Both HSP27 and HSP20 are actin binding proteins and may modulate smooth muscle relaxation by a direct interaction with actin or with actin associated proteins. Thus, we hypothesize that HSP20 and HSP27 co-ordinately regulate the intrinsic tone of smooth muscle and this regulation is dependent on the phosphorylation and macromolecular associations of the two small heat shock proteins.
The specific aims of this investigation are to: 1. Characterize the interactions of HSP20 with the smooth muscle contractile apparatus and determine the role these interactions in mediating vasorelaxation. 2. Determine the mechanisms by which phosphorylated HSP27 inhibits the phosphorylation of HSP20 and muscle relaxation. These studies will elucidate the molecular mechanisms of cyclic nucleotide-dependent relaxation and vasospasm due to impaired relaxation and may lead to more direct pharmacologic approaches to the treatment of vasospastic disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058027-07
Application #
6537304
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Barouch, Winifred
Project Start
1997-04-05
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
7
Fiscal Year
2002
Total Cost
$289,000
Indirect Cost

  Institution

Name
Arizona State University-Tempe Campus
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
188435911
City
Tempe
State
AZ
Country
United States
Zip Code
85287

  Publications

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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