| First Author | Chen C | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 8 | Pages | 2916-27 |
| PubMed ID | 22772469 | Mgi Jnum | J:190074 |
| Mgi Id | MGI:5447910 | Doi | 10.1172/JCI60387 |
| Citation | Chen C, et al. (2012) Integrin alpha9beta1 in airway smooth muscle suppresses exaggerated airway narrowing. J Clin Invest 122(8):2916-27 |
| abstractText | Exaggerated contraction of airway smooth muscle is the major cause of symptoms in asthma, but the mechanisms that prevent exaggerated contraction are incompletely understood. Here, we showed that integrin alpha9beta1 on airway smooth muscle localizes the polyamine catabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT) in close proximity to the lipid kinase PIP5K1gamma. As PIP5K1gamma is the major source of PIP2 in airway smooth muscle and its activity is regulated by higher-order polyamines, this interaction inhibited IP3-dependent airway smooth muscle contraction. Mice lacking integrin alpha9beta1 in smooth muscle had increased airway responsiveness in vivo, and loss or inhibition of integrin alpha9beta1 increased in vitro airway narrowing and airway smooth muscle contraction in murine and human airways. Contraction was enhanced in control airways by the higher-order polyamine spermine or by cell-permeable PIP2, but these interventions had no effect on airways lacking integrin alpha9beta1 or treated with integrin alpha9beta1-blocking antibodies. Enhancement of SSAT activity or knockdown of PIP5K1gamma inhibited airway contraction, but only in the presence of functional integrin alpha9beta1. Therefore, integrin alpha9beta1 appears to serve as a brake on airway smooth muscle contraction by recruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1gamma. Targeting key components of this pathway could thus lead to new treatment strategies for asthma. |
