Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle

2000 ◽  
Vol 278 (2) ◽  
pp. L329-L334 ◽  
Author(s):  
Ahmad Boota ◽  
Bruce Johnson ◽  
Kee-L Lee ◽  
Michelle A. Blaskovich ◽  
Shang-Xi Liu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Inflammatory Cytokine ◽  
Vascular Reactivity ◽  
Superoxide Production ◽  
Platelet Derived Growth Factor ◽  
Nitric Oxide Production ◽  
Farnesyltransferase Inhibitor ◽  
Superoxide Generation

We recently showed that the farnesyltransferase inhibitor FTI-277 blocks interleukin 1β (IL-1β)-induced nitric oxide production in pulmonary vascular smooth muscle cells (SMC), whereas the geranylgeranyltransferase inhibitor GGTI-298 enhances this effect. Here we show that IL-1β and platelet-derived growth factor (PDGF) stimulate superoxide production by pulmonary vascular SMC and that this effect is blocked by both FTI-277 and GGTI-298, suggesting that farnesylated and geranylgeranylated proteins are required for superoxide production. We also show that FTI-277 and GGTI-298 block superoxide production stimulated by constitutively active mutant H-Ras. Furthermore, superoxide production by IL-1β, PDGF factor, and constitutively activated Ras is blocked by diphenyleneiodonium, implicating NAD(P)H oxidase as the generating enzyme. Given the role of oxidant radicals in vascular reactivity and injury, the action of both FTI-277 and GGTI-298 in suppressing superoxide generation by an inflammatory cytokine as well as by a potent smooth muscle mitogen may be therapeutically useful.

scholarly journals Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling

2010 ◽  
Vol 299 (3) ◽  
pp. H673-H679 ◽  
Author(s):  
Anna E. Dikalova ◽  
María Carolina Góngora ◽  
David G. Harrison ◽  
J. David Lambeth ◽  
Sergey Dikalov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Smooth Muscle ◽  
Superoxide Production ◽  
Ang Ii ◽  
Wild Type ◽  
Superoxide Generation ◽  
Enos Uncoupling ◽  
Endothelium Dependent Relaxation

Recent work has made it clear that oxidant systems interact. To investigate potential cross talk between NADPH oxidase (Nox) 1 upregulation in vascular smooth muscle and endothelial function, transgenic mice overexpressing Nox1 in smooth muscle cells (TgSMCnox1) were subjected to angiotensin II (ANG II)-induced hypertension. As expected, NADPH-dependent superoxide generation was increased in aortas from Nox1-overexpressing mice. Infusion of ANG II (0.7 mg·kg−1·day−1) for 2 wk potentiated NADPH-dependent superoxide generation and hydrogen peroxide production compared with similarly treated negative littermate controls. Endothelium-dependent relaxation was impaired in transgenic mice, and bioavailable nitric oxide was markedly decreased. To test the hypothesis that eNOS uncoupling might contribute to endothelial dysfunction, the diet was supplemented with tetrahydrobiopterin (BH4). BH4 decreased aortic superoxide production, partially restored bioavailable nitric oxide in aortas of ANG II-treated TgSMCnox1 mice, and significantly improved endothelium-dependent relaxation in these mice. Western blot analysis revealed less dimeric eNOS in TgSMCnox1 mice compared with the wild-type mice; however, total eNOS was equivalent. Pretreatment of mouse aortas with the eNOS inhibitor NG-nitro-l-arginine methyl ester decreased ANG II-induced superoxide production in TgSMCnox1 mice compared with wild-type mice, indicating that uncoupled eNOS is also a significant source of increased superoxide in transgenic mice. Thus overexpression of Nox1 in vascular smooth muscle leading to enhanced production of reactive oxygen species in response to ANG II causes eNOS uncoupling and a decrease in nitric oxide bioavailability, resulting in impaired vasorelaxation.

Defective autophagy in vascular smooth muscle cells alters contractility and Ca2+ homeostasis in mice

2015 ◽  
Vol 308 (6) ◽  
pp. H557-H567 ◽  
Author(s):  
Cédéric F. Michiels ◽  
Paul Fransen ◽  
Dorien G. De Munck ◽  
Guido R. Y. De Meyer ◽  
Wim Martinet
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Vascular Smooth Muscle ◽  
Vascular Reactivity ◽  
Contractile Function ◽  
Cell Types ◽  
Resting Membrane Potential ◽  
Plasmic Reticulum ◽  
Old Mice

Autophagy is an evolutionary preserved process that prevents the accumulation of unwanted cytosolic material through the formation of autophagosomes. Although autophagy has been extensively studied to understand its function in normal physiology, the role of vascular smooth muscle (SM) cell (VSMC) autophagy in Ca2+ mobilization and contraction remains poorly understood. Recent evidence shows that autophagy is involved in controlling contractile function and Ca2+ homeostasis in certain cell types. Therefore, autophagy might also regulate contractile capacity and Ca2+-mobilizing pathways in VSMCs. Contractility (organ chambers) and Ca2+ homeostasis (myograph) were investigated in aortic segments of 3.5-mo-old mice containing a SM cell-specific deletion of autophagy-related 7 ( Atg7; Atg7 fl/ fl SM22α -Cre+ mice) and in segments of corresponding control mice ( Atg7+/+ SM22α -Cre+). Our results indicate that voltage-gated Ca2+ channels (VGCCs) of Atg7 fl/ fl SM22α -Cre+ VSMCs were more sensitive to depolarization, independent of changes in resting membrane potential. Contractions elicited with K+ (50 mM) or the VGCC agonist BAY K8644 (100 nM) were significantly higher due to increased VGCC expression and activity. Interestingly, the sarcoplasmic reticulum of Atg7 fl/ fl SM22α -Cre+ VSMCs was enlarged, which, combined with increased sarco(endo)plasmic reticulum Ca2+-ATPase 2 expression and higher store-operated Ca2+ entry, promoted inositol 1,4,5-trisphosphate-mediated contractions of Atg7 fl/ fl SM22α -Cre+ segments and maximized the Ca2+ storing capacity of the sarcoplasmic reticulum. Moreover, decreased plasma membrane Ca2+-ATPase expression in Atg7 fl/ fl SM22α -Cre+ VSMCs hampered Ca2+ extrusion to the extracellular environment. Overall, our study indicates that defective autophagy in VSMCs leads to an imbalance between Ca2+ release/influx and Ca2+ reuptake/extrusion, resulting in higher basal Ca2+ concentrations and significant effects on vascular reactivity.

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