title: Pulsatile equibiaxial stretch inhibits thrombin-induced RhoA and NF-kappaB activation.
abstract: This study investigated interactions between the effects of mechanical stretch and thrombin on RhoA activation in rat aortic smooth muscle cells (RASMC). Equibiaxial, pulsatile stretch, or thrombin produced a significant increase in RhoA activation. Surprisingly, in combination, 30 min of stretch inhibited the ability of thrombin to activate RhoA. NO donors and 8-bromo-cGMP significantly inhibited thrombin-induced RhoA activation. Interestingly, the nitric oxide synthase (NOS) inhibitor L-NAME increased basal RhoA activity, suggesting that NOS activity exerts a tonic inhibition on RhoA. Stretching RASMC increases nitrite production, consistent with the idea that NO contributes to the inhibitory effects of stretch. Thrombin stimulates MAP kinase and NF-kappaB pathways through Rho and these responses were blocked by 8-bromo-cGMP or stretch and restored by L-NAME. These data suggest that stretch, acting through NO and cGMP, can prevent the ability of thrombin to stimulate Rho signaling pathways that contribute to pathophysiological proliferative and inflammatory responses.
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-00435, USA. jhaga@bioeng.ucsd.edu
authors.forename: Jason H
authors.initials: JH
authors.lastname: Haga
authors.forename: Roland
authors.initials: R
authors.lastname: Kaunas
authors.forename: Julie
authors.initials: J
authors.lastname: Radeff-Huang
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Weems
authors.forename: Kristine D
authors.initials: KD
authors.lastname: Estrada
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Seasholtz
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013718:Tensile Strength; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester