Pulsatile equibiaxial stretch inhibits thrombin-induced RhoA and NF-kappaB activation.
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.
Haga
Jason H
JH
Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-00435, USA. jhaga@bioeng.ucsd.edu
Kaunas
Roland
R
Radeff-Huang
Julie
J
Weems
Jessica M
JM
Estrada
Kristine D
KD
Chien
Shu
S
Brown
Joan Heller
JH
Seasholtz
Tammy M
TM
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
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