Tyrosine kinase inhibitors suppress endotoxin- and IL-1 beta-induced NO synthesis in aortic smooth muscle cells

1993 ◽  
Vol 265 (3) ◽  
pp. H1014-H1018 ◽  
Author(s):  
N. Marczin ◽  
A. Papapetropoulos ◽  
J. D. Catravas
Keyword(s):  
Smooth Muscle ◽  
Tyrosine Kinase ◽  
Smooth Muscle Cells ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Muscle Cells ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle

Nitric oxide (NO) formation via the expression of an endotoxin- and cytokine-inducible NO synthase (iNOS) within the vascular smooth muscle is thought to be responsible for the cardiovascular collapse that occurs during septic shock and antitumor therapy with cytokines. Because the molecular mechanisms that underlie induction of iNOS are still unclear and because tyrosine kinases are implicated in interleukin-1 beta (IL-1 beta)-induced prostaglandin synthesis in mesangial cells and in NO generation by an insulinoma cell line, we investigated the influence of tyrosine kinase inhibitors on iNOS induction in cultured rat aortic smooth muscle cells (RASMC). The production of biologically active NO was demonstrated by L-arginine-dependent guanosine 3',5'-cyclic monophosphate (cGMP) accumulation after a 3-h exposure to either IL-1 beta or lipopolysaccharide (LPS). Pretreatment of RASMC for 30 min with the tyrosine kinase inhibitor genistein prevented both IL-1 beta- and LPS-elicited cGMP accumulation in a concentration-dependent manner. Geldanamycin, a chemically different tyrosine kinase inhibitor, also blocked cGMP formation in response to both LPS and IL-1 beta at nanomolar concentrations. Genistein and geldanamycin inhibited cGMP accumulation even when added 90 min after LPS exposure, but no inhibition was observed when they were included at later time points (120-180 min), suggesting that the inhibitors had no direct effect on iNOS activity after its induction. Formation of cGMP in response to sodium nitroprusside and to NO released from bovine aortic endothelial cells remained virtually unaffected by genistein and geldanamycin.(ABSTRACT TRUNCATED AT 250 WORDS)

H2O2-induced egr-1, fra-1, and c-jun gene expression is mediated by tyrosine kinase in aortic smooth muscle cells

2000 ◽  
Vol 29 (8) ◽  
pp. 736-746 ◽  
Author(s):  
Najia Jin ◽  
Nathan D Hatton ◽  
Maureen A Harrington ◽  
Xiaolin Xia ◽  
Steve H Larsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Tyrosine Kinase ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle

Attenuation of endothelin-1-induced calcium response by tyrosine kinase inhibitors in vascular smooth muscle cells

1996 ◽  
Vol 270 (6) ◽  
pp. C1825-C1833 ◽  
Author(s):  
C. Y. Liu ◽  
M. Sturek
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tyrosine Kinase ◽  
Smooth Muscle Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Muscle Cells ◽  
Endothelin 1 ◽  
Fura 2

Although tyrosine kinases play an important role in cell growth and have been implicated in regulation of smooth muscle contraction, their role in agonist-induced myoplasmic Ca2+ responses is unclear. We examined effects of the tyrosine kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) on the endothelin-1 (ET-1)-induced Ca2+ response and determined underlying mechanisms for the effects. Freshly isolated smooth muscle cells from porcine coronary arteries were loaded with fura 2 ester, and myoplasmic free Ca2+ (Ca2+ (m)) concentration was estimated with fura 2 microfluorometry. Both genistein and MDHC inhibited the initial transient Cam2+ response to ET by 54 and 81%, respectively (P < 0.05), in the presence of extracellular Ca2+. Genistein also significantly delayed the Cam2+ response, with the latent period from ET-1 application to the beginning of the Cam2+ response being increased from 1.08 +/- 0.17 to 2.65 +/- 0.52 min (P < 0.05). In the absence of extracellular Ca2+, genistein inhibited the ET-1-induced Cam2+ response by 93% (P < 0.05). The Cam2+ responses to caffeine (5 mM) or inositol trisphosphate (IP3) applied intracellularly via a patch-clamp pipette were not affected by genistein. Both genistein and MDHC also abolished the sustained Cam2+ response to ET-1. However, the Cam2+ response to depolarization by 80 mM K+ was not inhibited by MDHC and only inhibited 22% by genistein (P < 0.05). These results indicate that 1) activation of tyrosine kinases is an important regulatory mechanism for the ET-1-induced Cam2+ response in vascular smooth muscle and 2) tyrosine kinases mediate ET-1-induced Ca2+ release with no direct effect on IP3-mediated Ca2+ release. Thus ET-1-mediated signaling upstream of IP3 interaction with the Ca2+ stores is regulated by tyrosine kinases.

scholarly journals Progesterone Induces RhoA Inactivation in Male Rat Aortic Smooth Muscle Cells Through Up-Regulation of p27kip1

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4473-4482 ◽  
Author(s):  
Hui-Chen Wang ◽  
Wen-Sen Lee
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Muscle Cells ◽  
Mitogen Activated Protein Kinase ◽  
Male Rat ◽  
Migration Inhibition ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle

Abstract Previously, we showed that progesterone (P4) at physiologic concentrations (5nM–500nM) inhibits proliferation and migration of rat aortic smooth muscle cells (RASMCs). The P4-induced migration inhibition in RASMC was resulted from Rat sacroma homolog gene family, member A (RhoA) inactivation induced by activating the cSrc/AKT/ERK 2/p38 mitogen-activated protein kinase-mediated signaling pathway. We also demonstrated that up-regulation of cyclin-dependent kinase inhibitor 1B (p27kip1) is involved in the P4-induced migration inhibition in RASMC. Because P4 can increase formation of the p27kip1-RhoA complex in RASMC, this finding led us to hypothesize that the P4-induced inactivation in RhoA might be caused by up-regulation of p27kip1. Here, we showed that P4 increased phosphorylation of p27kip1 at Ser10 in the nucleus, which in turn caused p27kip1 translocation from the nucleus to the cytosol, subsequently increasing formation of the p27kip1-RhoA complex. These effects were blocked by knocking-down kinase-interacting stathmin (KIS) using KIS small interfering RNA. Knock-down of p27kip1 abolished the P4-induced decreases in the level of RhoA protein in RASMC. However, pretreatment of RASMC with the proteasome inhibitor, N-(benzyloxycarbonyl)leucinylleucinylleucinal (MG132), prevented the P4-induced degradation of p27kip1 and RhoA. Taken together, our investigation of P4-induced migration inhibition in RASMC showed a sequence of associated intracellular events that included 1) increase in formation of the KIS-p27kip1 complex in the nucleus; 2) phosphorylated nuclear p27kip1 at Ser10; 3) increased cytosolic translocation of p27kip1 and formation of the p27kip1-RhoA complex in the cytosol; and 4) degradation of p27kip1 and RhoA through the ubiquitin-proteasome pathway. These findings highlight the molecular mechanisms underlying P4-induced migration inhibition in RASMC.

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