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J. Biol. Chem., Vol. 283, Issue 26, 17946-17953, June 27, 2008

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Examination of the Cellular Mechanisms by Which Marinobufagenin Inhibits Cytotrophoblast Function^*

Mohammad N. Uddin, Darijana Horvat, Shannon S. Glaser, Brett M. Mitchell, and Jules B. Puschett¹

From the Divisions of Nephrology and Hypertension and Gastroenterology, Department of Medicine, Texas A&M Health Science Center, Scott and White Clinic, Temple, Texas 76508

Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in the inhibition of Na⁺/K⁺-ATPase. Increased plasma levels have been reported in patients with volume expansion-related hypertension. We have recently demonstrated that MBG impairs first trimester cytotrophoblast (CTB) cell proliferation, migration, and invasion, which may play a role in the development of preeclampsia. However, whether apoptosis contributes to altered CTB cell function by MBG remains unknown. Using the human extravillous CTB cell line SGHPL-4, we examined the effect of MBG and a similar Na⁺/K⁺-ATPase inhibitor, ouabain, on the phosphorylation status of Jnk, p38, and Src. Additionally, we measured apoptosis by caspase 9 and 3/7 activity and by annexin-V staining. We also investigated interleukin-6 (IL-6) secretion with or without p38 and Jnk inhibition. MBG significantly increased the phosphorylation of Jnk, p38, and Src and increased the expression of caspase 9 and 3/7 indicating the activation of apoptosis. MBG treatment also stimulated the expression of the early apoptosis marker, annexin-V, which was prevented by Jnk and p38 inhibition. MBG also stimulated the secretion of IL-6, which was attenuated by p38 inhibition. Ouabain had similar effects to those of MBG, suggesting that the apoptotic effects on CTB cells may be mediated by inhibition of Na⁺/K⁺-ATPase. In conclusion, the MBG-induced impairment of CTB function occurs via activation of Jnk, p38, and Src leading to increased apoptosis and IL-6 secretion. These observations may have clinical applicability with respect to the therapy of preeclampsia.

Received for publication, February 5, 2008 , and in revised form, April 11, 2008.

^* This work was supported in part by a research grant-in-aid from Dialysis Clinic, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 2401 South 31st St., Rm. 407L, Temple, TX 76508. Fax: 254-724-8344; E-mail: jpuschett{at}swmail.sw.org.

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