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Intimations on the Pathophysiology of Human Preterm Labor: The Unique Actions of Nitric Oxide in the Myometrium and the Consequences of its Dysregulation
AuthorBarnett, Scott D.
AdvisorBuxton, Iain L.O.
Biochemistry and Molecular Biology
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Approximately 12% of all infants are born prematurely in the United States, costing in excess of 26 billion dollars annually. About half of those preterm births are the result of spontaneous preterm labor (sPTL), which is idiopathic in nature. One of the reasons so many cases of sPTL result in preterm birth is because tocolytics, which are drugs that prevent or halt labor, are only effective at delaying birth by 48-hours. This failure of tocolytics is due in part to the unique nature of uterine smooth muscle. Specifically, we have found that global cGMP accumulation, or depletion, has little effect on nitric oxide-mediated myometrial relaxation. This observation has generally been overlooked during tocolytic development in favor of pursuing therapeutics that modulate canonical pathways; however, this peculiarity of the myometrium may reveal the importance of the direct action of nitric oxide to modify proteins via S-nitrosation, a labile posttranslational modification whose dysregulation is associated with many diseases. Unlike term human myometrium, nitric oxide’s effects are not only blunted in sPTL myometrium, but global protein S-nitrosations are also diminished, suggesting a dysfunctional response to nitric oxide-mediated protein S-nitrosation. Our study of S-nitrosoglutathione reductase (GSNOR), an enzyme that degrades the common endogenous form of nitric oxide, S-nitrosoglutathione (GSNO), reveals increased expression of the enzyme in sPTL myometrium, associated with decreased total protein S-nitrosation. Inhibition of GSNOR by N6022 relaxes myometrial tissue,iindicating the importance of nitric oxide donors and protein S-nitrosation in myometrial quiescence. GSNO, which can trans-S-nitrosate proteins, also alters acto-myosin ATP-ase activity, increases TREK-1 outwardly rectifying potassium currents, and increases myosin light chain kinase activity. Taken together, these findings offer novel explanations for nitric oxide-mediated relaxation in myometrium, and provide evidence for the effectiveness of a new class of tocolytics.