: Vascular smooth muscle relaxation is typically hypothesized to be the reversal of activation, i.e. reduction of myoplasmic [Ca2+] myosin regulatory light chain (MRLC) dephosphorylation. We term this form of relaxation as """"""""deactivation"""""""" because it is the reversal of activation mechanisms. Some stimuli induce a relaxation that dose not involve """"""""deactivation"""""""" mechanisms. Elevations in [cGMP] or [cAMP] can reduce smooth muscle tone despite persistent elevations in MRLC phosphorylation levels. We term this process 'force suppression' to separate it from deactivation mechanisms which reduce force by reducing MRCL phosphorylation.In this proposal, we present evidence suggesting that the mechanism responsible for 'force suppression' involves binding of phosphorylate p20 (also known as heat shock protein 20 or HSP20) to smooth muscle thin filaments. We have preliminary data that recombinant phosphorylated p20 suppresses force in skinned carotid artery. We also have preliminary data that force suppression is not associated with reductions in shortening velocity. This suggests that force suppression is mediated at the crossbridge level. To further study this phenomenon, we propose to study recombinant mutant p20 in skinned carotid artery and to perform detailed muscle mechanics in intact carotid artery.
Thee aims are:
Aim 1. Test the hypothesis that phosphorylated p20 specifically suppresses skinned smooth muscle force via the actin binding domain contained in the peptide p20 (110-121). This p20 domain has a high sequence homology with a domain in troponin 1 called the inhibitory peptide.
Aim 2. Test the hypothesis that force suppression is regulated by p20 phosphorylation at serine 16.
Aim 3. Test the hypothesis that force suppression is mediated at the crossbridge level.Inappropriate responses of smooth muscle are involved in most morbidity and mortality in the developed world. Many current treatments target smooth muscle to reduce tone. It is possible that targeting the force suppression pathway (i.e. p20) might provide comparable benefits.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071191-02
Application #
6637821
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Lin, Michael
Project Start
2002-06-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$333,000
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Tejani, Ankit D; Walsh, Michael P; Rembold, Christopher M (2011) Tissue length modulates ""stimulated actin polymerization,"" force augmentation, and the rate of swine carotid arterial contraction. Am J Physiol Cell Physiol 301:C1470-8
Meeks, M K; Han, S; Tucker, A L et al. (2008) Phospholemman does not participate in forskolin-induced swine carotid artery relaxation. Physiol Res 57:669-75
Rembold, Christopher M; Tejani, Ankit D; Ripley, Marcia L et al. (2007) Paxillin phosphorylation, actin polymerization, noise temperature, and the sustained phase of swine carotid artery contraction. Am J Physiol Cell Physiol 293:C993-1002
Rembold, Christopher M; Meeks, Melissa K; Ripley, Marcia L et al. (2007) Longer muscle lengths recapitulate force suppression in swine carotid artery. Am J Physiol Heart Circ Physiol 292:H1065-70
Rembold, Christopher M (2007) Force suppression and the crossbridge cycle in swine carotid artery. Am J Physiol Cell Physiol 293:C1003-9
Batts, Timothy W; Klausner, Adam P; Jin, Zhicheng et al. (2006) Increased expression of heat shock protein 20 and decreased contractile stress in obstructed rat bladder. J Urol 176:1679-84
Meeks, Melissa K; Ripley, Marcia L; Jin, Zhicheng et al. (2005) Heat shock protein 20-mediated force suppression in forskolin-relaxed swine carotid artery. Am J Physiol Cell Physiol 288:C633-9
Murphy, Richard A; Rembold, Christopher M (2005) The latch-bridge hypothesis of smooth muscle contraction. Can J Physiol Pharmacol 83:857-64
Frobert, O; Buus, C L; Rembold, C M (2005) HSP20 phosphorylation and interstitial metabolites in hypoxia-induced dilation of swine coronary arteries. Acta Physiol Scand 184:37-44
Batts, Timothy W; Walker, John S; Murphy, Richard A et al. (2005) Absence of force suppression in rabbit bladder correlates with low expression of heat shock protein 20. BMC Physiol 5:16

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