Submitted on March 16, 2007
Accepted on July 17, 2007
CAT-2 Amplifies The Agonist-Evoked Force Of Airway Smooth Muscle By Enhancing Spermine-Mediated Phosphatidylinositol(4)-Phosphate 5-Kinase-
Activity
Hang Chen1, Carol L MacLeod2, Bijia Deng1, Lawrence Mason3, Marion Kasaian1, Samuel Goldman3, Stan Wolf3, Cara Williams3, and Michael R Bowman1*
1 Inflammation, Wyeth Research, CAmbridge, Massachusetts, United States
2 Cancer Center, University California SD, La Jolla, California, United States
3 Inflammation, Wyeth Research, Cambridge, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: mrbowman{at}wyeth.com.
We investigated the effect the loss of the CAT-2 gene (CAT-2-/-) has on lung resistance (RL) and tracheal isometric tension. The RL of CAT-2-/- mice at a maximal dose of acetylcholine (ACh) was decreased by 33.66% (p = 0.05, n = 8) as compared with that of C57BL/6 (B6) mice. The isometric tension of tracheal rings from CAT-2 -/- mice showed a significant decrease in carbachol (CCh)-induced force generation (33.01%, p < 0.05, n = 8) as compared to controls. The isoproterenol (ISO)- or the sodium nitroprusside (SNP)-induced relaxation was not affected in tracheal rings from CAT-2-/- mice. The activity of iNOS and arginase in lung tissue lysates of CAT-2-/- mice were indistinguishable from that of B6 mice. Further, the expression of phospholipase-C-
(PLC-) and phosphatidylinositol-(4)-phosphate-5-kinase-
(PIP-5K-) was examined in the lung tissue of CAT-2-/- and B6 mice. The expression of PIP-5K- but not PLC- was significantly reduced in CAT-2-/- compared to B6 mice. The reduced airway smooth muscle (ASM) contractility to CCh seen in the CAT-2-/- tracheal rings was completely reversed by pre-treating the rings with 100 µM spermine. This increase in the CAT-2-/- tracheal ring contraction upon spermine pretreatment correlated with a recovery of the expression of PIP-5K-. Our data indicates that CAT-2 exerts control over ASM force development through a spermine-dependent pathway which directly correlates with the expression level of PIP-5K- in the lung.
