Nitric oxide triggers mammary gland involution after weaning: remodelling is delayed but not impaired in mice lacking inducible nitric oxide synthase

2010 ◽  
Vol 428 (3) ◽  
pp. 451-462 ◽  
Author(s):  
Rosa Zaragozá ◽  
Ana Bosch ◽  
Concha García ◽  
Juan Sandoval ◽  
Eva Serna ◽  
...  

During mammary gland involution, different signals are required for apoptosis and tissue remodelling. To explore the role of NO in the involution of mammary tissue after lactation, NOS2 (inducible nitric oxide synthase)-KO (knockout) mice were used. No apparent differences were observed between NOS2-KO and WT (wild-type) animals during pregnancy and lactation. However, upon cessation of lactation, a notable delay in involution was observed, compared with WT mice. NOS2-KO mice showed increased phosphorylation of STAT (signal transducer and activator of transcription) 5 during weaning, concomitant with increased β-casein mRNA levels when compared with weaned WT glands, both hallmarks of the lactating period. In contrast, activation of STAT3, although maximal at 24 h after weaning, was significantly reduced in NOS2-KO mice. STAT3 and NF-κB (nuclear factor κB) signalling pathways are known to be crucial in the regulation of cell death and tissue remodelling during involution. Indeed, activation of both STAT3 and NF-κB was observed in WT mice during weaning, concomitant with an increased apoptotic rate. During the same period, less apoptosis, in terms of caspase 3 activity, was found in NOS2-KO mice and NF-κB activity was significantly reduced when compared with WT mice. Furthermore, the activation of the NF-κB signalling pathway is delayed in NOS2-KO mice when compared with WT mice. These results emphasize the role of NO in the fine regulation of the weaning process, since, in the absence of NOS2, the switching on of the cascades that trigger involution is hindered for a time, retarding apoptosis of the epithelial cells and extracellular matrix remodelling.

Circulation ◽  
1997 ◽  
Vol 96 (9) ◽  
pp. 3104-3111 ◽  
Author(s):  
Yoshihiro Fukumoto ◽  
Hiroaki Shimokawa ◽  
Toshiyuki Kozai ◽  
Toshiaki Kadokami ◽  
Kouichi Kuwata ◽  
...  

2007 ◽  
Vol 103 (3) ◽  
pp. 1045-1055 ◽  
Author(s):  
Juliann G. Kiang ◽  
Phillip D. Bowman ◽  
Xinyue Lu ◽  
Yansong Li ◽  
Brian W. Wu ◽  
...  

Hemorrhage has been shown to increase inducible nitric oxide synthase (iNOS) and deplete ATP levels in tissues and geldanamycin limits both processes. Moreover, it is evident that inhibition of iNOS reduces caspase-3 and increases survival. Thus we sought to identify the molecular events responsible for the beneficial effect of geldanamycin. Hemorrhage in mice significantly increased caspase-3 activity and protein while treatment with geldanamycin significantly limited these increases. Similarly, geldanamycin inhibited increases in proteins forming the apoptosome (a complex of caspase-9, cytochrome c, and Apaf-1). Modulation of the expression of iNOS by iNOS gene transfection or siRNA treatment demonstrated that the level of iNOS correlates with caspase-3 activity. Our data indicate that geldanamycin limits caspase-3 expression and protects from organ injury by suppressing iNOS expression and apoptosome formation. Geldanamycin, therefore, may prove useful as an adjuvant in fluids used to treat patients suffering blood loss.


Hepatology ◽  
2002 ◽  
Vol 35 (2) ◽  
pp. 289-298 ◽  
Author(s):  
Mohammed Bourdi ◽  
Yasuhiro Masubuchi ◽  
Timothy P. Reilly ◽  
Hamid R. Amouzadeh ◽  
Jackie L. Martin ◽  
...  

Nitric Oxide ◽  
2000 ◽  
pp. 811-821 ◽  
Author(s):  
Victoria Kolb-Bachofen ◽  
Klaus-Dietrich Kröncke ◽  
Karin Fehsel ◽  
Christoph Suschek

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